The leukotriene signaling pathway: a druggable target in Alzheimer’s disease Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-18 Johanna Michael, Julia Marschallinger, Ludwig Aigner
The underlying pathology of Alzheimer’s disease (AD) is complex and includes, besides amyloid beta (Aβ) plaque depositions and neurofibrillary tangles, brain atrophy and neurodegeneration, neuroinflammation, impaired neurogenesis, vascular and blood–brain barrier (BBB) disruptions, neurotransmitter disbalances, and others. Here, we hypothesize that such complex pathologies can only be targeted efficiently through pleiotropic approaches. One interesting drug target is the leukotriene pathway, which mediates various aspects of AD pathology. Approaching this pathway at different levels with genetic and pharmacological tools demonstrated beneficial outcomes in several in vivo studies using different mouse models of AD. Here, we review the current literature on the leukotriene signaling pathway as a target for drug development in AD.
Lost medicines: a longer view of the pharmaceutical industry with the potential to reinvigorate discovery Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-14 Michael S. Kinch, Grant A. Kinch, Rebekah H. Griesenauer
It is widely understood that the 1962 Kefauver–Harris Amendment to the Food, Drug and Cosmetics Act ushered in the modern regulation of medicines requiring a combination of safety and efficacy. However, fewer appreciate the amendment was applied retroactively to virtually all medicines sold in the USA. For various reasons, many medicines faded into history. Here, we identify and analyze >1600 medicines (including over-the-counter drugs) and their innovators prior to the enactment of Kefauver–Harris. We report 880 of these past medicines are no longer accessible. This project also reveals new insight into the pharmaceutical enterprise, which reveals an industry already mature and beginning to retract before enactment of the legislation. Beyond its historical implications, the recollection of these medicines could offer potential starting points for the future development of much-needed drugs.
The future of drug development: the paradigm shift towards systems therapeutics Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-10 Meindert Danhof, Kevin Klein, Pieter Stolk, Murray Aitken, Hubert Leufkens
Progress in cell biology, genetics, molecular, and systems pharmacology is the driving force behind a current paradigm shift in drug research. This paradigm shift shapes new avenues for advanced treatments that are commonly referred to as ‘systems therapeutics’. Systems therapeutics differ in many ways from current drugs because they target biological networks rather than single transduction pathways, and affect disease processes rather than physiological processes. Here, we examine how the paradigm shift towards systems therapeutics will change current scientific concepts of the interactions between drugs and diseases, the organization of research and development, as well as the clinical use and therapeutic evaluations of therapeutic interventions.
Do urocortins have a role in treating cardiovascular disease? Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-10 Ekaterini Chatzaki, Nikoleta Kefala, Ioannis Drosos, Fani Lalidou, Stavroula Baritaki
Corticotropin-releasing factor (CRF) and the three homolog neuropeptides, urocortin (UCN) 1, 2 and 3, are the major neuroendocrine factors implicated in the response of the body to stress. Recent evidence suggests that UCNs have a significant role in the pathogenesis and management of cardiovascular disease, such as congestive heart failure, ischemic heart disease, and hypertension. These data led to the initiation of clinical trials testing a possible role of UCNs in the diagnosis and therapy of cardiovascular disease, with encouraging results. Here, we summarize the available literature concerning the role of UCNs in the cardiovascular system, focusing on the emerging data creating a potential for clinical applications.
3D in vitro models of tumors expressing EGFR family receptors: a potent tool for studying receptor biology and targeted drug development Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-08 Evgeniya A. Sokolova, Vladimir V. Vodeneev, Sergey M. Deyev, Irina V. Balalaeva
A well-tolerated and rapidly acting thiopurine for IBD? Drug. Discov. Today (IF 6.848) Pub Date : 2018-09-07 Timothy H.J. Florin, John D. Wright, Siddharth D. Jambhrunkar, Michael G. Henman, Amirali Popat
Thiopurine drugs continue to be a cornerstone of inflammatory bowel disease (IBD) treatment. Thiopurines are economical compared with many newer medical treatments for IBD, other chronic inflammatory diseases and leukaemia, although they are not without their shortcomings. These include a slow-onset therapeutic action and many adverse drug reactions. This feature article surveys published data, unpublished in vitro and in vivo experiments, as well as clinical experience, underpinning a rationale for bringing a novel thiopurine drug formulation to market. This formulation has a rapid action making it suitable for the induction and maintenance treatment of IBD and avoids most thiopurine-associated adverse reactions.
The use of nanoparticles as biomaterials in dentistry Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-31 Ranjeet A. Bapat, Chaitanya P. Joshi, Prachi Bapat, Tanay V. Chaubal, Rohit Pandurangappa, Naveen Jnanendrappa, Bapi Gorain, Sukant Khurana, Prashant Kesharwani
Maintenance of oral health is a major challenge in dentistry. Different materials have been used to treat various dental diseases, although treatment success is limited by features of the biomaterials used. To overcome these limitations, materials incorporated with nanoparticles (NPs) can be used in dental applications including endodontics, periodontics, tissue engineering, oral surgery, and imaging. The unique properties of NPs, including their surface:volume ratio, antibacterial action, physical, mechanical, and biological characteristics, and unique particle size have rendered them effective vehicles for dental applications. In this review, we provide insights into the various applications of NPs in dentistry, including their benefits, limitations, properties, actions and future potential.
Cnidarian peptide neurotoxins: a new source of various ion channel modulators or blockers against central nervous systems disease Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-27 Qiwen Liao, Yu Feng, Binrui Yang, Simon Ming-Yuen Lee
Cnidaria provide the largest source of bioactive peptides for new drug development. The venoms contain enzymes, potent pore-forming toxins and neurotoxins. The neurotoxins can immobilize predators rapidly when discharged via modifying sodium-channel-gating or blocking the potassium channel during the repolarization stage. Most cnidarian neurotoxins remain conserved under the strong influence of negative selection. Neuroactive peptides targeting the central nervous system through affinity with ion channels could provide insight leading to drug treatment of neurological diseases, which arise from ion channel dysfunctions. Although marine resources offer thousands of possible peptides, only one peptide derived from Cnidaria: ShK-186, also named dalazatide, has reached the pharmaceutical market. This review focuses on neuroprotective agents derived from cnidarian neurotoxic peptides.
Advancing precision medicine with personalized drug screening Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-17 Kirill Gorshkov, Catherine Z. Chen, Raisa E. Marshall, Nino Mihatov, Yong Choi, Dac-Trung Nguyen, Noel Southall, Kevin Chen, John K. Park, Wei Zheng
Personalized drug screening (PDS) of approved drug libraries enables rapid development of specific small-molecule therapies for individual patients. With a multidisciplinary team including clinicians, researchers, ethicists, informaticians and regulatory professionals, patient treatment can be optimized with greater efficacy and fewer adverse effects by using PDS as an approach to find remedies. In addition, PDS has the potential to rapidly identify therapeutics for a patient suffering from a disease without an existing therapy. From cancer to bacterial infections, we review specific maladies addressed with PDS campaigns. We predict that PDS combined with personal genomic analyses will contribute to the development of future precision medicine endeavors.
Nanoengineered delivery systems for cancer imaging and therapy: recent advances, future directions and patent evaluation Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-16 Ghazal Nabil, Ketki Bhise, Samaresh Sau, Mohamed Atef, Hossny A. El-Banna, Arun K. Iyer
Cancer is the second-highest cause of death worldwide. Several therapeutic approaches, such as conventional chemotherapy, antibodies and small-molecule inhibitors and nanotherapeutics, have been employed in battling cancer. Among them, nanotheranostics is an example of successful personalized medicine bearing the dual role of early diagnosis and therapy to cancer patients. In this review, we focus on various types of theranostic polymer and metal nanoparticles for their roles in cancer therapy and imaging concerning their limitations and future applications, such as dendritic cell cancer vaccination, gene delivery, T cell activation and immune modulation. Some of the recorded patent applications and clinical trials are illustrated and the impact of the biological microenvironment on the biodistribution and accumulation of nanoparticles is also discussed.
New leads for drug repurposing against malaria Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-09 Nila Madassary Pazhayam, Jyoti Chhibber-Goel, Amit Sharma
Malaria is threatening a resurgence because of drug resistance against frontline artemisinin-based combination therapies (ACTs). This necessitates the development of alternate routes for malaria treatment. Here, we present a refined focus on US Food and Drug Administration (FDA)-approved over-the-counter (OTC) drugs that could be repurposed. We analyzed the growth inhibition data for Plasmodium falciparum and Plasmodium berghei in context of 189 and 37 drugs (total of 226), respectively. Of these, our analyses revealed 18 currently used drugs that would be suitable for further development as potential antimalarials. Eight identified drugs share enzymatic targets between the human host and the malaria parasite, providing a platform for mechanistic and drug selectivity studies that could provide optimized leads as next-generation antimalarials.
Selection of protein conformations for structure-based polypharmacology studies Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-10 Luca Pinzi, Fabiana Caporuscio, Giulio Rastelli
Effects of antidiabetic drugs on NLRP3 inflammasome activity, with a focus on diabetic kidneys Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-04 Habib Yaribeygi, Niki Katsiki, Alexandra E. Butler, Amirhossein Sahebkar
Inflammatory responses have a pivotal role in the development of diabetic nephropathy (DN). The nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is a newly recognized and potent inflammatory mediator that induces inflammatory responses in several disorders, including DN. The suppression of procytokine release and inflammatory response is integral to the prevention of complications arising from the inflammatory process. In this review, we discuss the role of the NLRP3 inflammasome in the pathogenesis of DN, focusing on its effects on interleukin (IL)-1β and IL-18. Furthermore, we review the potential anti-inflammatory effects of antidiabetic drugs used in routine clinical practice, such as insulin, biguanides, Sodium-glucose co-transporter-2 (SGLT2) inhibitors, sulfonylureas, thiazolidinediones, and dipeptidyl peptidase-4 (DPP-4) inhibitors. In addition, we discuss whether these drugs can also modulate NLRP3 inflammasome activity in renal tissues.
Copies of nonbiological complex drugs: generic, hybrid or biosimilar? Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-04 Paolo Rocco, Umberto M. Musazzi, Silvia Franzè, Paola Minghetti
Turning straw into gold: building robustness into gene signature inference Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-04 Wilson Wen Bin Goh, Limsoon Wong
Reproducible and generalizable gene signatures are essential for clinical deployment, but are hard to come by. The primary issue is insufficient mitigation of confounders: ensuring that hypotheses are appropriate, test statistics and null distributions are appropriate, and so on. To further improve robustness, additional good analytical practices (GAPs) are needed, namely: leveraging existing data and knowledge; careful and systematic evaluation of gene sets, even if they overlap with known sources of confounding; and rigorous testing of inferred signatures against as many published data sets as possible. Here, using a re-examination of a breast cancer data set and 48 published signatures, we illustrate the value of adopting these GAPs.
Discovering novel valid biomarkers and drugs in patient-centric genomic trials: the new epoch of precision surgical oncology Drug. Discov. Today (IF 6.848) Pub Date : 2018-08-02 Demosthenes E. Ziogas, Ioannis D. Kyrochristos, Dimitrios H. Roukos
Despite standardization of multimodal treatment and approval of several targeted drugs for resectable, non-metastatic cancer (M0 patients), intrinsic and acquired resistance and relapse rates remain high, even in early-stage aggressive tumors. Genome analysis could overcome these unmet needs. Our comprehensive review underlines the controversy on stable or spatiotemporally evolving clones as well as promising yet inconclusive data on genome-based biomarkers and drug development. We propose clinicogenomic trials in M0 patients for the validation of intratumor heterogeneity (ITH), circulating genomic subclones (cGSs) and intra-patient genomic heterogeneity (IPGH) as biomarkers and simultaneous discovery of novel oncotargets. This evidence-based strategy highlights the coming of precision surgical oncology with a future perspective of understanding and disrupting deregulated transcriptional networks.
Translational in vitro research: integrating 3D drug discovery and development processes into the drug development pipeline Drug. Discov. Today (IF 6.848) Pub Date : 2018-07-30 Jens M. Kelm, M. Lal-Nag, G.S. Sittampalam, Marc Ferrer
As we witness steady progress towards the development of robust, scalable, and reproducible 3D tissue models for preclinical drug testing, there is a need for systematic physiological and pharmacological validation and benchmarking. Ongoing and future studies should generate evidence as to whether 3D tissue models are more predictive, help reduce the risk of failure rate, and can be used for decision making in the drug discovery and development pipeline. Here, we discuss the importance of harmonizing the validation of these models based on throughput capacity and physiological complexity as a requirement to establish their true translational capacity. We also outline our strategy for a novel 3D-tailored holistic drug discovery concept rather than piecemeal integration of 3D models into the current process.
Patent term restoration for top-selling drugs in the USA Drug. Discov. Today (IF 6.848) Pub Date : 2018-07-25 Reed F. Beall, Jonathan Darrow, Aaron S. Kesselheim
Patents temporarily protect brand-name drugs from generic competition, but some of the 20-year patent term is used up before marketing approval. To compensate for patent life lost to clinical testing and regulatory review, current law provides patent term restoration (PTR) of up to 5 years. Examining 170 top-selling drugs approved between 2000 and 2012, we found that 49% (83 drugs) received a PTR extension (median extension: 2.75 years) yielding a median total exclusivity period of 13.75 years, compared with 10.0 years for the 87 nonextended drugs. Because PTR substantially prolongs market exclusivity periods, policies that extend non-patent exclusivity periods (which generally run concurrently with patent exclusivity) for less than the extended patent terms of drugs will have little practical impact.
Streamlining nonclinical drug development using the FDA 505(b)(2) new drug application regulatory pathway Drug. Discov. Today (IF 6.848) Pub Date : 2018-07-21 William F. Salminen, Marc E. Wiles, Ruth E. Stevens
In the USA, drugs are approved by the FDA by three main regulatory pathways: (i) 505(b)(1) new drug applications (NDAs); (ii) 505(b)(2) NDAs; and (iii) 505(j) abbreviated NDAs (ANDAs). The appropriate pathway depends on the active ingredient, already approved drug products, drug formulation, clinical indication, route of exposure, among other factors. The 505(b)(2) NDA pathway is a regulatory approval pathway that allows sponsors to use existing public data in lieu of conducting studies; thus, potentially offering significant drug development and marketing advantages. Nonclinical testing programs for 505(b)(2) submissions are often reduced and, in some cases, are not even required. This paper provides an overview of the 505(b)(2) regulatory pathway with a focus on how nonclinical programs can be streamlined and accelerated.
Updates on the pathogenicity status of Pseudomonas aeruginosa Drug. Discov. Today (IF 6.848) Pub Date : 2018-07-20 Mohd W. Azam, Asad U. Khan
Pseudomonas aeruginosa is a pathogenic bacterial species that causes infections and diseases in both plants and animals, including several human diseases, especially in immune-compromised patients, and many hospital-acquired infections. Given that P. aeruginosa is an opportunistic pathogen, the occurrence of antimicrobial resistance makes it difficult to treat and eradicate. Antimicrobial resistance in P. aeruginosa is categorized as intrinsic, acquired, or adaptive. Here, we different aspects of resistance and pathogenicity in P. aeruginosa, such as the role of outer membrane proteins, transcriptional regulators, efflux pumps, enzymes, and biofilms in antimicrobial resistance. We also highlight quorum-sensing (QS) genes, their protein secretion, and role in pathogenicity; different QS inhibitors; and the influence of QS on the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system and virulence factor production.
MCR-1: a promising target for structure-based design of inhibitors to tackle polymyxin resistance Drug. Discov. Today (IF 6.848) Pub Date : 2018-07-20 Soo Jung Son, Renjie Huang, Christopher J. Squire, Ivanhoe K.H. Leung
The spread of a novel mobile colistin resistance gene (mcr1) has jeopardised the use of polymyxins, last-resort antibiotics that are used increasingly to treat infections caused by multidrug-resistant (MDR) Gram-negative pathogens. In early 2017, the WHO reported the global spread of mcr1 within a few years after its initial discovery in China. The protein encoded by mcr1 is a putative 60-kDa phosphoethanolamine (pEtN) transferase, MCR-1, and has been studied extensively since its discovery. Herein, we present a comprehensive review of MCR-1 covering its structure, function, and mechanism, to call for the rational drug design of molecular inhibitors of MCR-1 to use in colistin-based combination therapies.
Polycomb repressive complex 2 inhibitors: emerging epigenetic modulators Drug. Discov. Today (IF 6.848) Pub Date : 2018-07-19 Danish Uddin, Naidu Subbarao, Mohammad Faheem, Shahper Nazir Khan
Polycomb repressive complex 2 (PRC2) plays a significant part in histone methylation − trimethylating K27 at H3, an epigenetic hallmark of gene silencing. Inhibition of PRC2 has been reported as a promising strategy for the treatment of various cancers. Significant efforts have been made toward the development of PRC2 inhibitors and some of them have progressed to clinical trials. The binding mode of these inhibitors is well understood. Here, we summarize the advances in drug discovery and development for PRC2 component inhibitors by focusing on their chemotypes, activity, selectivity and binding modes. We believe that such analysis will provide new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform.
How soon will digital endpoints become a cornerstone for future drug development? Drug. Discov. Today (IF 6.848) Pub Date : 2018-07-17 Philip Boehme, Arne Hansen, Ronenn Roubenoff, Joseph Scheeren, Maximilian Herrmann, Thomas Mondritzki, Jan Ehlers, Hubert Truebel
Digital technologies are transforming healthcare and will provide the basis for more patient-centric innovation in the pharmaceutical industry. Digital endpoints in clinical studies have the potential to drive innovation and reduce costly late-stage failures. This is also currently under consideration by regulatory agencies, such as the US Food and Drug Administration (FDA). The academic–industrial collaboration MOBILISED-D aims to implement and validate real-world walking speed (RWS) as a digital endpoint accepted by regulatory authorities as a first of its class. Previous work has shown that loss of mobility driven by chronic illness and frailty in older patients can be a relevant readout or effect of different diseases and various organ systems.
The emerging role of copper-64 radiopharmaceuticals as cancer theranostics Drug. Discov. Today (IF 6.848) Pub Date : 2018-04-07 Alessandra Boschi, Petra Martini, Emilija Janevik-Ivanovska, Adriano Duatti
Copper radionuclides are rapidly emerging as potential diagnostic and therapeutic tools in oncology, particularly 64Cu-radiopharmaceuticals for targeting neuroendocrine, prostate, and hypoxic tumors. Unexpectedly, experimental results are also revealing the impressive biological behavior of simple [64Cu2+] ions. For example, it has been demonstrated that administration of ionic [64Cu2+] in physiological solution allows the selective targeting of a variety of malignancies. These remarkable biological properties appear to be crucially linked to the natural role of copper ions in cell proliferation. Here, we review the current status of 64Cu-radiopharmaceuticals in molecular imaging and cancer therapy.
NTM drug discovery: status, gaps and the way forward Drug. Discov. Today (IF 6.848) Pub Date : 2018-04-07 Mu-Lu Wu, Dinah B. Aziz, Véronique Dartois, Thomas Dick
Incidence of pulmonary diseases caused by non-tuberculous mycobacteria (NTM), relatives of Mycobacterium tuberculosis, is increasing at an alarming rate, surpassing tuberculosis in many countries. Current chemotherapies require long treatment times and the clinical outcomes are often disappointing. There is an urgent medical need to discover and develop new, more-efficacious anti-NTM drugs. In this review, we summarize the current status of NTM drug development, and highlight knowledge gaps and scientific obstacles in NTM drug discovery. We propose strategies to reduce biological uncertainties and to begin to populate a NTM drug pipeline with attractive leads and drug candidates.
An operational model for GPCR homodimers and its application in the analysis of biased signaling Drug. Discov. Today (IF 6.848) Pub Date : 2018-04-09 Bin Zhou, Jesús Giraldo
G-protein-coupled receptors are one of the most important protein superfamilies as drug targets in drug discovery programs. Their interactions with ligands are influenced by their homomerization. In this study, we propose an operational model for receptor homodimers, which includes constitutive receptor activity. Distinct functional response curves can be obtained from this model, which can satisfactorily depict typical complex experimental data as biphasic and bell-shaped curves. Operational parameters in the model can provide mechanistic explanations for observed functional complexity associated with the cooperativity and intrinsic efficacy of ligands. Because the model presented here is derived from the conceptual framework of operational models, it takes advantage of the body of knowledge coming from the widespread use of this type of modeling. The operational homodimer model can also explain the biased signaling dependent on ligand concentration. In conclusion, this operational homodimer model has a wide range of applications in pharmacological research.
The remarkable therapeutic potential of response-based dose individualisation in drug trials and patient care Drug. Discov. Today (IF 6.848) Pub Date : 2018-04-12 Chao Chen
The FDA reported that most drugs are effective in only 25–62% of patients. Although many drugs require dose individualisation in clinical practice, dose-finding trials usually aim to identify an optimal dose for the patient population. Such a dose would be suboptimal for many patients. Simulations show that individualised dose titration, balancing efficacy against toxicity, can remarkably increase the response rate — doubling it in some situations. Dose titration in a clinical trial can efficiently establish the realistic expectations for the drug’s true utility in a trial setting that reflects clinical practice, as well as generate important knowledge to guide patient care through informative drug labels. This design answers key questions truly relevant to patient care that other designs cannot — will a patient benefit from a given therapy, to what extent and at what dose? Therefore, response-based dose titration should be considered for dose-finding trials, where appropriate, for drugs that will eventually be used this way in the clinic.
Role of lncRNAs in ovarian cancer: defining new biomarkers for therapeutic purposes Drug. Discov. Today (IF 6.848) Pub Date : 2018-04-23 Manish K. Tripathi, Kyle Doxtater, Fatemeh Keramatnia, Chidi Zacheaus, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan
Long noncoding RNAs (lncRNAs) are a class of noncoding RNA, involved in regulation of diverse physiological and pathological processes. Ovarian cancer is the leading cause of death among all gynecological malignancies in the world and its underlying mechanism is still unclear. LncRNAs exhibit multiple biological functions in various stages of ovarian cancer development. We will discuss and summarize the new and important lncRNAs and their involvement in disease, which might represent promising therapeutic targets. Therapeutic intervention based on silencing or functional inhibition of target lncRNAs will be beneficial for ovarian cancer patients.
Human pharmacological approaches to TRP-ion-channel-based analgesic drug development Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-30 Iris Weyer-Menkhoff, Jörn Lötsch
The discovery of novel analgesic drug targets is an active research topic owing to insufficient treatment options for persisting pain. Modulators of temperature-sensing transient receptor potential ion channels (thermoTRPs), in particular TRPV2, TRPV1, TRPM8 and TRPA1, have reached clinical development. This requires access for TRP channels and the effects of specific modulators in humans. This is currently possible via (i) the study of TRP channel function in human-derived cell lines, (ii) immunohistochemical visualization of TRP channel expression in human tissues, (iii) human experimental pain models employing sensitization by means of topical application of TRP channel activators including capsaicin (TRPV1), menthol (TRPM8), mustard oil and cinnamaldehyde (TRPA1), and (iv) the study of phenotypic consequences of human TRP gene variants.
Mapping genes for drug chronotherapy Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-28 Kun Wei, Qian Wang, Jingwen Gan, Shilong Zhang, Meixia Ye, Claudia Gragnoli, Rongling Wu
Genome-wide association studies have been increasingly used to map and characterize genes that contribute to interindividual variation in drug response. Some studies have integrated the pharmacokinetic (PK) and pharmacodynamic (PD) processes of drug reactions into association mapping, gleaning new insight into how genes determine the dynamic relationship of drug effect and drug dose. Here, we present an evolutionary framework by which two distinct concepts, chronopharmacodynamics and heterochrony (describing variation in the timing and rate of developmental events), are married to comprehend the pharmacogenetic architecture of drug response. The resulting new concept, heterochronopharmacodynamics (HCPD), can better interpret how genes influence drug efficacy and drug toxicity according to the circadian rhythm of the body and changes in drug concentration.
Marketing authorisation applications submitted to the European Medicines Agency by small and medium-sized enterprises: an analysis of major objections and their impact on outcomes Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-25 Nadia Amaouche, Hélène Casaert Salomé, Olivier Collignon, Mariana Roldao Santos, Constantinos Ziogas
Small and medium-sized enterprises (SMEs) are an important source of innovative medicines. Compared with their larger counterparts, they experience challenges as a result of insufficient human and financial resources that can hamper drug development and regulatory compliance. This analysis reviews the profile of major objections raised in applications for medicines for human use submitted by SMEs to the European Medicines Agency between 2011 and 2015 and their impact on the outcome of applications. It showed that SMEs experience challenges in the quality (e.g., manufacturing process validation and on control and/or characterisation data of drug substance or drug product) and the clinical sections of marketing authorisation applications (e.g., analysis or robustness of pivotal data or selection of submitted studies, study design issues and marginal or no clinical relevant efficacy), with deficiencies in demonstrating clinical efficacy representing the major eventual hurdles to authorisation.
Delivery systems of local anesthetics in bone surgery: are they efficient and safe? Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-26 Manon Dupleichs, Qiman Gao, Zahi Badran, Pascal Janvier, Jean-Michel Bouler, Olivier Gauthier, Faleh Tamimi, Elise Verron
Management of postoperative pain following bone surgery includes administration of local anesthetics (LAs). Smart delivery systems, including triggered systems, have been designed to provide a continuous release of LA in situ. However, these systems can provide a high level of LA locally. This review will examine the state-of-the-art regarding the LA delivery systems optimized for management of postoperative pain in bone surgery and will discuss the potential adverse effects of LAs on the overall pathways of bone healing, including the inflammation response phase, hemostasis phase, tissue repair phase and remodeling phase. There is a clinical need to document these effects and the potential impacts on the clinical outcome of the patient.
Importance of target-mediated drug disposition for small molecules Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-19 Dennis A. Smith, Robert A.B. van Waterschoot, Neil J. Parrott, Andrés Olivares-Morales, Thierry Lavé, Malcolm Rowland
Target concentration is typically not considered in drug discovery. However, if targets are expressed at relatively high concentrations and compounds have high affinity, such that most of the drug is bound to its target, in vitro screens can give unreliable information on compound affinity. In vivo, a similar situation will generate pharmacokinetic (PK) profiles that deviate greatly from those normally expected, owing to target binding affecting drug distribution and clearance. Such target-mediated drug disposition (TMDD) effects on small molecules have received little attention and might only become apparent during clinical trials, with the potential for data misinterpretation. TMDD also confounds human microdosing approaches by providing therapeutically unrepresentative PK profiles. Being aware of these phenomena will improve the likelihood of successful drug discovery and development.
The A–Z of Zika drug discovery Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-20 Melina Mottin, Joyce V.V.B. Borba, Rodolpho C. Braga, Pedro H.M. Torres, Matheus C. Martini, Jose Luiz Proenca-Modena, Carla C. Judice, Fabio T.M. Costa, Sean Ekins, Alexander L. Perryman, Carolina Horta Andrade
Despite the recent outbreak of Zika virus (ZIKV), there are still no approved treatments, and early-stage compounds are probably many years away from approval. A comprehensive A–Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial to advancing the fight against the Zika virus and other flaviviruses but also helps us prepare for the next emerging virus outbreak to which we will have to respond.
Neural network and deep-learning algorithms used in QSAR studies: merits and drawbacks Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-21 Fahimeh Ghasemi, Alireza Mehridehnavi, Alfonso Pérez-Garrido, Horacio Pérez-Sánchez
The inherent risks associated with newly traded biopharmaceutical firms Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-21 David R. Williams, Trent J. Spaulding
Here, we provide a comprehensive study related to the risks of all biopharmaceutical firms going public in the USA between 1996 and 2015. We found 355 firms that met our requirements for being in the sector that focuses on creating drugs for humans. Collectively, these firms spent approximately US$86.9 billion on research and development (R&D) during this time. They also lost approximately US$69.3 billion in combined net income. We also examine the delisting of these firms from a public market, their number of collaborators at the initial public offering (IPO), and estimate the percentage ownership by other biopharmaceutical firms at the IPO.
U-BIOPRED: evaluation of the value of a public–private partnership to industry Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-21 John H. Riley, Veit J. Erpenbeck, J.G. Matthews, C.T.J. Holweg, C. Compton, W. Seibold, T. Higenbottam, S.S. Wagers, A. Rowe, D. Myles
Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) was initiated in the first year of the Innovative Medicines Initiative (IMI). It was an ambitious plan to tackle the understanding of asthma through an integration of clinical and multi-’omics approaches that necessitated the bringing together of industry, academic, and patient representatives because it was too large to be managed by any one of the partners in isolation. It was a novel experience for all concerned. In this review, we describe the main features of the U-BIOPRED experience from the industry perspective. We list some of the key advantages and learnings from the perspective of the authors, and also improvements that we feel could be made in future projects.
Small-molecule inhibitors of macrophage migration inhibitory factor (MIF) as an emerging class of therapeutics for immune disorders Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-21 Tjie Kok, Anna A. Wasiel, Robbert H. Cool, Barbro N. Melgert, Gerrit J. Poelarends, Frank J. Dekker
Macrophage migration inhibitory factor (MIF) is an important cytokine for which an increasing number of functions is being described in the pathogenesis of inflammation and cancer. Nevertheless, the availability of potent and druglike MIF inhibitors that are well-characterized in relevant disease models remains limited. Highly potent and selective small-molecule MIF inhibitors and validation of their use in relevant disease models will advance drug discovery. In this review, we provide an overview of recent advances in the identification of MIF as a pharmacological target in the pathogenesis of inflammatory diseases and cancer. We also give an overview of the current developments in the discovery and design of small-molecule MIF inhibitors and define future aims in this field.
Human-specific approaches to brain research for the 21 st century: a South American perspective Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-13 Marcia Triunfol, Stevens Rehen, Marina Simian, Troy Seidle
The 21 st century paradigm in toxicology, which emphasizes mechanistic understanding and species-relevant modeling of human biology and pathophysiology, is gaining traction in the wider biosciences through a global workshop series organized by the BioMed21 Collaboration. The second of this series, entitled Emerging Technology Toward Pathway-Based Human Brain Research, was held in Brazil in 2017, bringing together leading South American and international scientists, research funders and other stakeholders. The aims were to foster strategic scientific dialogue and identify actionable consensus recommendations as a first step toward a roadmap for 21 st century, human-specific health research and funding in the region.
Retinal pigment epithelial cells as a therapeutic tool and target against retinopathies Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-13 Barbara Pavan, Alessandro Dalpiaz
Retinal pigment epithelium (RPE) is a cell monolayer essential for photoreceptor function and forming the blood–retinal barrier. RPE and retinal neurons share the same origin and a polarized cytoarchitecture. Several factors determine the phagocytosis and permeability of RPE, influencing photoreceptor renewal and drug delivery, efficacy and toxicity. Adult human RPE expresses neuronal markers in vitro, indicating a potential transdifferentiation. Degeneration of the RPE leads to death of photoreceptors and retinal neurons, resulting in the vision loss of retinopathy. Here, we suggest tools for cell engineering to discover new ways for activating the endogenous regeneration of barrier functions and/or of the retinal precursors in RPE cells.
Pragmatic clinical trials: ethical imperatives and opportunities Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-12 Shona Kalkman, Ghislaine J.M.W. van Thiel, Diederick E. Grobbee, Johannes J.M. van Delden
Pragmatic clinical trials generate robust real-world evidence that holds great potential to better inform decision making regarding new medicines. For clinicians, patients and regulators, this evidence would preferably be available sooner rather than later. This means that, ideally, market authorization of any given medicine is accompanied by evidence obtained from a pragmatic trial. Given the operational and regulatory complexities of pragmatic trials in general, stakeholders tend to be hesitant to employ more pragmatism at the time of market approval. One prominent hurdle for the conduct of pragmatic trials is the concern that pragmatic design features conflict with ethical standards for clinical trials. To encourage timely yet responsible generation of real-world evidence through clinical trials, it is important to delineate exactly which areas, from a societal point of view, demand early pragmatic evaluations. We also urge stakeholders to recognize how the current system of trial ethics oversight already accommodates for more-pragmatic approaches, and how new ideas about their permissibility have progressed in the bioethics literature.
Drugp-Induced Rhabdomyolysis Atlas (DIRA) for idiosyncratic adverse drug reaction management Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-11 Zhining Wen, Yu Liang, Yingyi Hao, Brian Delavan, Ruili Huang, Mike Mikailov, Weida Tong, Menglong Li, Zhichao Liu
Drug-induced rhabdomyolysis (DIR) is an idiosyncratic and fatal adverse drug reaction (ADR) characterized in severe muscle injuries accompanied by multiple-organ failure. Limited knowledge regarding the pathophysiology of rhabdomyolysis is the main obstacle to developing early biomarkers and prevention strategies. Given the lack of a centralized data resource to curate, organize, and standardize widespread DIR information, here we present a Drug-Induced Rhabdomyolysis Atlas (DIRA) that provides DIR-related information, including: a classification scheme for DIR based on drug labeling information; postmarketing surveillance data of DIR; and DIR drug property information. To elucidate the utility of DIRA, we used precision dosing, concomitant use of DIR drugs, and predictive modeling development to exemplify strategies for idiosyncratic ADR (IADR) management.
Why are there no drugs indicated for sciatica, the most common chronic neuropathic syndrome of all? Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-09 John D. Markman, Ralf Baron, Jennifer S. Gewandter
Here, we examine the stark contrast between the successes and failures of the clinical development of analgesics for different types of chronic low back pain (CLBP) syndrome over the past three decades. Multiple drugs with differing mechanisms of action have been developed for nonspecific axial-predominant low back syndromes and yet not a single therapy is indicated for any neuropathic low back pain syndrome (e.g., sciatica). Clinician findings have informed the entry criteria for neuropathic low back pain clinical trials, whereas entry criteria of axial CLBP trials have prioritized only patient reports of pain. This key difference could account for the lack of success in developing therapies for neuropathic low back pain in an era marked by successful development of analgesics for other types of CLBP as well as many chronic pain syndromes associated with nerve injury, such as post-herpetic neuralgia (PHN).
Interrogating the microbiome: experimental and computational considerations in support of study reproducibility Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-08 Carine Poussin, Nicolas Sierro, Stéphanie Boué, James Battey, Elena Scotti, Vincenzo Belcastro, Manuel C Peitsch, Nikolai V. Ivanov, Julia Hoeng
Therapeutic application of antibody fragments in autoimmune diseases: current state and prospects Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-08 João C Fernandes
Over the past decades, conventional antibodies have been dissected through different strategies into smaller antigen-binding fragments. Therapeutic solutions built on such fragments can offer several advantages, including the capacity to access challenging epitopes, reduced immunogenicity, lower production costs, and higher stability. Although the development of antibody fragments for cancer therapy has received more attention than any other potential therapeutic application, the development of pharmacological tools based on these molecules for the treatment of autoimmune diseases (AIDs) has been growing at a fast pace. Here, I provide an in-depth characterization of the various formats for the treatment of autoimmune diseases in development across the industry, including antigen-binding fragments (Fab), single-chain variable fragments (scFv), and single variable-domain fragments, as well as multimeric antibody fragments and antibody–drug conjugates.
The fruit fly Drosophila melanogaster as an innovative preclinical ADME model for solute carrier membrane transporters, with consequences for pharmacology and drug therapy Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-08 Yiwen Wang, Bernard Moussian, Elke Schaeffeler, Matthias Schwab, Anne T. Nies
Solute carrier membrane transporters (SLCs) control cell exposure to small-molecule drugs, thereby contributing to drug efficacy and failure and/or adverse effects. Moreover, SLCs are genetically linked to various diseases. Hence, in-depth knowledge of SLC function is fundamental for a better understanding of disease pathophysiology and the drug development process. Given that the model organism Drosophila melanogaster (fruit fly) expresses SLCs, such as for the excretion of endogenous and toxic compounds by the hindgut and Malpighian tubules, equivalent to human intestine and kidney, this system appears to be a promising preclinical model to use to study human SLCs. Here, we systematically compare current knowledge of SLCs in Drosophila and humans and describe the Drosophila model as an innovative tool for drug development.
Translational strategy: humanized mini-organs Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-05 Duong T. Nguyen, Magnus Althage, Maria Chiara Magnone, Sepideh Heydarkhan-Hagvall
Mini-organs engineered from decellularized organs repopulated with human stem cells can transform preclinical model strategies in target validation and biomarker discovery. Recellularized organs are whole humanized organs with preserved native architecture, conformity of the organ, composition of extracellular matrix and vascular matrix structures. With mini-organ models further understanding of developmental biology and assessment of potential therapeutic targets can be elucidated utilizing human induced pluripotent stem cells. As a next step, co-cultured mini-organ models could simulate pharmacokinetics and pharmacodynamics in physiological and pathological conditions. By overcoming key challenges, the development of humanized mini-organs as integrated biotechnology can address the translational gaps between in vitro, ex vivo and in vivo systems for an elevated human target validation model.
Supermolecular drug challenge to overcome drug resistance in cancer cells Drug. Discov. Today (IF 6.848) Pub Date : 2018-06-04 Yasuhiko Onishi, Yuki Eshita, Rui-Cheng Ji, Takashi Kobayashi, Masayasu Onishi, Masaaki Mizuno, Jun Yoshida, Naoji Kubota
Computational prediction of chemical reactions: current status and outlook Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-03 Ola Engkvist, Per-Ola Norrby, Nidhal Selmi, Yu-hong Lam, Zhengwei Peng, Edward C. Sherer, Willi Amberg, Thomas Erhard, Lynette A. Smyth
Over the past few decades, various computational methods have become increasingly important for discovering and developing novel drugs. Computational prediction of chemical reactions is a key part of an efficient drug discovery process. In this review, we discuss important parts of this field, with a focus on utilizing reaction data to build predictive models, the existing programs for synthesis prediction, and usage of quantum mechanics and molecular mechanics (QM/MM) to explore chemical reactions. We also outline potential future developments with an emphasis on pre-competitive collaboration opportunities.
Quantitative metrics for drug–target ligandability Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-06 Sinisa Vukovic, David J. Huggins
Ligandability is a prerequisite for druggability and is a much easier concept to understand, model and predict because it does not depend on the complex pharmacodynamic and pharmacokinetic mechanisms in the human body. In this review, we consider a metric for quantifying ligandability from experimental data. We discuss ligandability in terms of the balance between effort and reward. The metric is evaluated for a standard set of well-studied drug targets – some traditionally considered to be ligandable and some regarded as difficult. We suggest that this metric should be used to systematically improve computational predictions of ligandability, which can then be applied to novel drug targets to predict their tractability.
Prediction of brain:blood unbound concentration ratios in CNS drug discovery employing in silico and in vitro model systems Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-13 Houfu Liu, Kelly Dong, Wandong Zhang, Scott G. Summerfield, Georg C. Terstappen
Redundancy in two major compound databases Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-17 Dimitar Yonchev, Dilyana Dimova, Dagmar Stumpfe, Martin Vogt, Jürgen Bajorath
Public repositories of compounds and activity data are of prime importance for pharmaceutical research in academic and industrial settings. Major databases have evolved over the years. Their growth is accompanied by an increasing tendency toward data sharing. This is a positive development but not without potential problems. Using ChEMBL and PubChem as examples, we show that crosstalk between databases also leads to substantial data redundancy that might not be obvious. Redundancy is an important issue because it biases data analysis and knowledge extraction and leads to inflated views of available compounds, assays and activity data. Going forward it will be important to further refine data exchange and deposition criteria and make redundancy as transparent as possible.
N-acylethanolamine hydrolyzing acid amidase inhibition: tools and potential therapeutic opportunities Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-19 Pauline Bottemanne, Giulio G. Muccioli, Mireille Alhouayek
N-acylethanolamines (NAEs) (e.g., N-palmitoylethanolamine, N-arachidonoylethanolamine, N-oleoylethanolamine) are bioactive lipids involved in many physiological processes including pain, inflammation, anxiety, cognition and food intake. Two enzymes are responsible for the hydrolysis of NAEs and therefore regulate their endogenous levels and effects: fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA). As discussed here, extensive biochemical characterization of NAAA was carried out over the years that contributed to a better understanding of NAAA enzymology. An increasing number of studies describe the synthesis and pharmacological characterization of NAAA inhibitors. Recent medicinal chemistry efforts have led to the development of potent and stable inhibitors that enable studying the effects of NAAA inhibition in preclinical disease models, notably in the context of pain and inflammation.
Computational modeling approaches to quantitative structure–binding kinetics relationships in drug discovery Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-21 Pier G. De Benedetti, Francesca Fanelli
Simple comparative correlation analyses and quantitative structure–kinetics relationship (QSKR) models highlight the interplay of kinetic rates and binding affinity as an essential feature in drug design and discovery. The choice of the molecular series, and their structural variations, used in QSKR modeling is fundamental to understanding the mechanistic implications of ligand and/or drug–target binding and/or unbinding processes. Here, we discuss the implications of linear correlations between kinetic rates and binding affinity constants and the relevance of the computational approaches to QSKR modeling.
EU decision-making for marketing authorization of advanced therapy medicinal products: a case study Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-21 Sofieke de Wilde, Delphi G.M. Coppens, Jarno Hoekman, Marie L. de Bruin, Hubert G.M. Leufkens, Henk-Jan Guchelaar, Pauline Meij
A comparative analysis of assessment procedures for authorization of all European Union (EU) applications for advanced therapy medicinal products (ATMPs) shows that negative opinions were associated with a lack of clinical efficacy and identified severe safety risks. Unmet medical need was often considered in positive opinions and outweighed scientific uncertainties. Numerous quality issues illustrate the difficulties in this domain for ATMP development. Altogether, it suggests that setting appropriate standards for ATMP authorization in Europe, similar to elsewhere, is a learning experience. The experimental characteristics of authorized ATMPs urge regulators, industry, and clinical practice to pay accurate attention to post-marketing risk management to limit patient risk. Methodologies for ATMP development and regulatory evaluations need to be continuously evaluated for the field to flourish.
Strategic R&D transactions in personalized drug development Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-21 Tomohiro Makino, Yeongjoo Lim, Kota Kodama
Although external collaboration capability influences the development of personalized medicine, key transactions in the pharmaceutical industry have not been addressed. To explore specific trends in interorganizational transactions and key players, we longitudinally surveyed strategic transactions, comparing them with other advanced medical developments, such as antibody therapy, as controls. We found that the financing deals of start-ups have surged over the past decade, accelerating intellectual property (IP) creation. Our correlation and regression analyses identified determinants of financing deals among alliance deals, acquisition deals, patents, research and development (R&D) licenses, market licenses, and scientific papers. They showed that patents positively correlated with transactions, and that the number of R&D licenses significantly predicted financing deals. This indicates, for the first time, that start-ups and investors lead progress in personalized medicine.
Can hi-jacking hypoxia inhibit extracellular vesicles in cancer? Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-22 Michelle C. Lowry, Lorraine O’Driscoll
Increasing evidence indicates that extracellular vesicles (EVs) are key players in undesirable cell–cell communication in cancer. However, the release of EVs is not unique to cancer cells; normal cells release EVs to perform physiological roles. Thus, selective inhibition of EV release from cancer cells is desirable. Hypoxia contributes to tumour development and aggressiveness. EV quantities and thus undesirable communications are substantially increased in hypoxia. Targeting hypoxia could selectively inhibit EV release from tumour cells without disturbing physiologically relevant EVs. The unfavourable association between hypoxia and EV release is evident in multiple tumour types; therefore, targeting hypoxia could have a broad therapeutic benefit.
Extension of quality-by-design concept to the early development phase of pharmaceutical R&D processes Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-27 Ildikó Csóka, Edina Pallagi, Tamás L. Paál
Update on the main use of biomaterials and techniques associated with tissue engineering Drug. Discov. Today (IF 6.848) Pub Date : 2018-03-30 Daniela Steffens, Daikelly I. Braghirolli, Natasha Maurmann, Patricia Pranke
Regenerative medicine involves the study of cells, signaling cues and biomatrices to restore normal function of tissues and organs. To develop the matrices for use in tissue engineering there are three main groups of biomaterials: (i) naturally derived materials; (ii) synthetic polymers; and (iii) decellularized organ or tissue scaffolds. These biomaterials, in various forms such as hydrogels, nanofibers and 3D scaffolds, among others, have been employed for different tissue regeneration purposes, with several techniques involved in their production, including rapid prototyping, tissue decellularization and electrospinning. In this review, the main topics of hydrogels, 3D printing and electrospun scaffolds, other biomaterials and decellularization and recellularization will be discussed.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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