Drug discovery programs have traditionally focused on small molecules (molecular weight of <500 g/mol). However, for a significant number of drug targets, classical approaches are not feasible. For example, proteins without well-defined or with shallow binding pockets (e.g., those mediating protein–protein interactions) are difficult targets and, in many cases, even considered “undruggable.” (1) In addition, the classical modulation of protein functions through small molecule agonists, antagonists, or inhibitors has inherent limitations due to its occupancy-based mode of action. (2,3) Therefore, biologicals, mainly antibodies, have gained importance in recent years. They are well suited for modulating extracellular targets with high potency and selectivity; however, owing to their low membrane permeability, they usually cannot be employed to address intracellular targets and typically lack peroral and brain bioavailability. With a dramatically growing knowledge in biology, and due to the limitations of classical approaches, novel strategies in medicinal chemistry and novel types of drugs/novel chemotypes (“new modalities”) have recently gained importance in drug research, discovery, and development. (3−6) New therapeutic modalities include nonclassical representatives of (but are not limited to) the following chemotypes:

• Nanobodies and (modified) antibodies
• Oligo- and polypeptides (e.g., stapled and modified peptides)
• Oligo- and polynucleotides (e.g., siRNAs, mRNAs, aptamers, gene therapeutics)
• Polyglycosides
• Macrocyclic molecules
• Drug conjugates (e.g., antibody–drug conjugates, drug–drug conjugates, fluorescence-labeled drugs)
• Targeted protein degraders (e.g., proteolysis-targeting chimeras (PROTACs) and molecular glues) that induce a chemical knockdown of proteins
• Cellular therapies.

Nanobodies and (modified) antibodies Oligo- and polypeptides (e.g., stapled and modified peptides) Oligo- and polynucleotides (e.g., siRNAs, mRNAs, aptamers, gene therapeutics) Polyglycosides Macrocyclic molecules Drug conjugates (e.g., antibody–drug conjugates, drug–drug conjugates, fluorescence-labeled drugs) Targeted protein degraders (e.g., proteolysis-targeting chimeras (PROTACs) and molecular glues) that induce a chemical knockdown of proteins Cellular therapies. These new modalities possess properties beyond Lipinski’s rule of five for classical (peroral) drugs (7) and allow extending the chemical space in drug discovery. Due to their particular physicochemical and pharmacokinetic properties, they come with specific challenges for medicinal chemists, (bio)analytical chemists, and pharmacologists. The joint Virtual Special Issue on new drug modalities will collect the latest developments in this field related to medicinal chemistry, pharmacology, and translational science. Authors can choose one of the sister journals to submit their manuscript, depending on its main focus. The Editors may also offer transfer in case one or the other journal appears to be more appropriate. The Virtual Special Issue format means that articles are placed into the next available regular journal issue shortly after acceptance, instead of being published in a dedicated issue. Once all articles for the collection have been accepted, they will be featured on a dedicated web page, giving additional exposure to each publication. Please consider the relevant instructions to authors before submitting a manuscript. For ACS Pharmacology & Translational Science, different types of articles related to the topic are welcome, including Articles, Letters, Reviews and Mini-Reviews, Perspectives, Viewpoints, and Drug Discovery Stories. ACS Medicinal Chemistry Letters invites Letters, Innovations, Topical Innovations, Technology Notes, Notes, and Viewpoints. Journal of Medicinal Chemistry is interested in receiving original Research Articles, Perspectives, or Drug Annotations. The submission deadline for all three journals is July 31, 2022. We are looking forward to your manuscripts. Please do not hesitate to send us a prepublication request in case you are not sure whether your manuscript would fit. The relevant journal offices can be reached via the following email addresses:

• ACS Medicinal Chemistry Letters: [email protected]
• ACS Pharmacology & Translational Science: [email protected]
• Journal of Medicinal Chemistry:[email protected]

ACS Medicinal Chemistry Letters: [email protected] ACS Pharmacology & Translational Science: [email protected] Journal of Medicinal Chemistry:[email protected] This article references 7 other publications.

中文翻译：

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药物化学、药理学和转化科学中的新药模式：Journal of Medicinal Chemistry、ACS Medicinal Chemistry Letters 和 ACS Pharmacology & Translational Science 联合虚拟特刊

传统上，药物发现计划侧重于小分子（分子量 <500 g/mol）。然而，对于大量的药物靶点，经典的方法是不可行的。例如，没有明确定义或具有浅结合口袋的蛋白质（例如，那些介导蛋白质-蛋白质相互作用的蛋白质）是困难的目标，在许多情况下，甚至被认为是“不可成药的”。(1) 此外，通过小分子激动剂、拮抗剂或抑制剂对蛋白质功能的经典调节由于其基于占用的作用模式而具有固有的局限性。(2,3) 因此，生物制品，主要是抗体，近年来变得越来越重要。它们非常适合以高效力和选择性调节细胞外靶标；然而，由于它们的膜渗透性低，它们通常不能用于解决细胞内靶标，并且通常缺乏口服和脑生物利用度。随着生物学知识的急剧增长，以及由于经典方法的局限性，药物化学和新型药物/新型化学型（“新模式”）的新策略最近在药物研究、发现和开发中变得越来越重要。(3-6) 新的治疗方式包括（但不限于）以下化学型的非经典代表：发现、开发。(3-6) 新的治疗方式包括（但不限于）以下化学型的非经典代表：发现、开发。(3-6) 新的治疗方式包括（但不限于）以下化学型的非经典代表：

• 纳米抗体和（修饰的）抗体
• 寡核苷酸和多肽（例如，钉合和修饰的肽）
• 寡核苷酸和多核苷酸（例如，siRNA、mRNA、适体、基因疗法）
• 多糖苷
• 大环分子
• 药物偶联物（例如，抗体-药物偶联物、药物-药物偶联物、荧光标记药物）
• 靶向蛋白质降解剂（例如，蛋白水解靶向嵌合体 (PROTAC) 和分子胶）诱导蛋白质的化学敲低
• 细胞疗法。

纳米抗体和（修饰的）抗体 寡核苷酸和多肽（例如订书钉和修饰肽） 寡核苷酸和多核苷酸（例如 siRNA、mRNA、适体、基因治疗剂） 多糖苷 大环分子 药物偶联物（例如，抗体-药物偶联物、药物 - 药物）偶联物、荧光标记药物） 靶向蛋白质降解剂（例如，蛋白水解靶向嵌合体 (PROTAC) 和分子胶）诱导蛋白质的化学敲低 细胞疗法。这些新模式具有超越 Lipinski 的经典（口服）药物五法则 (7) 的特性，并允许扩展药物发现中的化学空间。由于它们特殊的物理化学和药代动力学特性，它们给药物化学家、（生物）分析化学家和药理学家带来了特定的挑战。联合虚拟特刊新药模式将收集该领域与药物化学、药理学和转化科学相关的最新进展。作者可以选择姊妹期刊之一提交他们的手稿，具体取决于其主要关注点。如果一个或另一个期刊似乎更合适，编辑也可能会提供转让。虚拟特刊格式意味着文章在接受后不久就会被放入下一期可用的常规期刊中，而不是在专门的问题上发表。一旦该系列的所有文章都被接受，它们将被展示在一个专门的网页上，为每个出版物提供额外的曝光率。在提交手稿之前，请考虑对作者的相关说明。对于ACS 药理学和转化科学，欢迎与该主题相关的不同类型的文章，包括文章、信件、评论和迷你评论、观点、观点和药物发现故事。ACS 药物化学快报邀请快报、创新、专题创新、技术笔记、笔记和观点。Journal of Medicinal Chemistry有兴趣接收原始研究文章、观点或药物注释。三本期刊的投稿截止日期均为2022年7月31日，期待您的来稿。如果您不确定您的手稿是否适合，请随时向我们发送预发表请求。可以通过以下电子邮件地址联系相关期刊办公室：

• ACS 药物化学快报：[电子邮件保护]
• ACS 药理学与转化科学：[电子邮件保护]
• 药物化学杂志：[电子邮件保护]

ACS 药物化学快报：[email protected] ACS Pharmacology & Translational Science：[email protected] Journal of Medicinal Chemistry：[email protected]本文引用了 7 篇其他出版物。