Abstract
Malaria remains the leading cause of deaths globally, despite significant advancement towards understanding its epidemiology and availability of multiple therapeutic interventions. Poor efficacy of the approved vaccine, and the rapid emergence of antimalarial drug resistance, warrants an urgent need to expedite the process of development of new lead molecules targeting malaria. Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes crucial for ribosomal protein synthesis and are valid antimalarial targets. This study explores the prospects of (re-)positioning the repertoire of approved drugs and natural products as potential malarial aaRS inhibitors. Molecular docking of these two sets of small-molecules to lysyl-, prolyl-, and tyrosyl- synthetases from Plasmodium followed by a comparison of the top-ranking docked compounds against human homologs facilitated identification of promising molecular scaffolds. Raltitrexed and Cefprozil, an anticancer drug and an antibiotic, respectively, showed stronger binding to Plasmodium aaRSs compared to human homologs with > 4 kcal/mol difference in the docking scores. Similarly, a difference of ~ 3 kcal/mol in Glide scores was observed for docked Calcipotriol, a drug used for psoriasis treatment, against the two lysyl-tRNA synthetases. Natural products such as Dihydroxanthohumol and Betmidin, having aromatic rings as a substructure, showed preferential docking to the purine binding pocket in Plasmodium tyrosyl-tRNA synthetase as evident from the calculated change in binding free energies. We present detailed analyses of the calculated intermolecular interaction for all top-scoring docked poses. Overall, this study provides a compelling foundation to design and develop specific antimalarials.
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References
Adachi R, Okada K, Skene R, Ogawa K, Miwa M, Tsuchinaga K, Ohkubo S, Henta T, Kawamoto T (2017) Discovery of a novel prolyl-tRNA synthetase inhibitor and elucidation of its binding mode to the ATP site in complex with l-proline. Biochem Biophys Res Commun 488:393–399. https://doi.org/10.1016/j.bbrc.2017.05.064
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242. https://doi.org/10.1093/nar/28.1.235
Bhachoo J, Beuming T (2017) Investigating protein-peptide interactions using the schrödinger computational suite. In: Schueler-Furman O, London N (eds) Modeling peptide-protein interactions: methods and protocols. Springer, New York, pp 235–254. https://doi.org/10.1007/978-1-4939-6798-8_14
Bhatt TK, Khan S, Dwivedi VP, Banday MM, Sharma A, Chandele A, Camacho N, de Pouplana LR, Wu Y, Craig AG, Mikkonen AT, Maier AG, Yogavel M, Sharma A (2011) Malaria parasite tyrosyl-tRNA synthetase secretion triggers pro-inflammatory responses. Nat Commun 2:530
Bhullar KS, Lagarón NO, McGowan EM, Parmar I, Jha A, Hubbard BP, Rupasinghe HPV (2018) Kinase-targeted cancer therapies: progress, challenges and future directions. Mol Cancer 17:48. https://doi.org/10.1186/s12943-018-0804-2
D’Amato RJ, Loughnan MS, Flynn E, Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082–4085. https://doi.org/10.1073/pnas.91.9.4082
Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717
Fang P, Han H, Wang J, Chen K, Chen X, Guo M (2015) Structural basis for specific inhibition of tRNA synthetase by an ATP competitive inhibitor. Chem Biol 22:734–744. https://doi.org/10.1016/j.chembiol.2015.05.007
Firn RD, Jones CG (2003) Natural products–a simple model to explain chemical diversity. Nat Prod Rep 20:382–391
Francklyn CS, Mullen P (2019) Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics. J Biol Chem 294:5365–5385. https://doi.org/10.1074/jbc.REV118.002956
Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein−ligand complexes. J Med Chem 49:6177–6196. https://doi.org/10.1021/jm051256o
Goodman CD, Pasaje CFA, Kennedy K, McFadden GI, Ralph SA (2016) Targeting protein translation in organelles of the Apicomplexa. Trends Parasitol 32:953–965. https://doi.org/10.1016/j.pt.2016.09.011
Graziose R, Lila MA, Raskin I (2010) Merging traditional Chinese medicine with modern drug discovery technologies to find novel drugs and functional foods. Curr Drug Discov Technol 7:2–12. https://doi.org/10.2174/157016310791162767
Gregson A, Plowe CV (2005) Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev 57:117–145. https://doi.org/10.1124/pr.57.1.4
Herman JD, Pepper LR, Cortese JF, Estiu G, Galinsky K, Zuzarte-Luis V, Derbyshire ER, Ribacke U, Lukens AK, Santos SA, Patel V, Clish CB, Sullivan WJ, Zhou H, Bopp SE, Schimmel P, Lindquist S, Clardy J, Mota MM, Keller TL, Whitman M, Wiest O, Wirth DF, Mazitschek R (2015) The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target for drug development. Sci Transl Med 7:288ra77. https://doi.org/10.1126/scitranslmed.aaa3575
Hewitt SN, Dranow DM, Horst BG, Abendroth JA, Forte B, Hallyburton I, Jansen C, Baragaña B, Choi R, Rivas KL, Hulverson MA, Dumais M, Edwards TE, Lorimer DD, Fairlamb AH, Gray DW, Read KD, Lehane AM, Kirk K, Myler PJ, Wernimont A, Walpole C, Stacy R, Barrett LK, Gilbert IH, Van Voorhis WC (2017) Biochemical and structural characterization of selective allosteric inhibitors of the plasmodium falciparum drug target, Prolyl-tRNA-synthetase. ACS Infect Dis 3:34–44. https://doi.org/10.1021/acsinfecdis.6b00078
Hoepfner D, McNamara CW, Lim CS, Studer C, Riedl R, Aust T, McCormack SL, Plouffe DM, Meister S, Schuierer S, Plikat U, Hartmann N, Staedtler F, Cotesta S, Schmitt EK, Petersen F, Supek F, Glynne RJ, Tallarico JA, Porter JA, Fishman MC, Bodenreider C, Diagana TT, Movva NR, Winzeler EA (2012) Selective and specific inhibition of the Plasmodium falciparum Lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin. Cell Host Microbe 11:654–663. https://doi.org/10.1016/j.chom.2012.04.015
Idris OA, Wintola OA, Afolayan AJ (2019) Evaluation of the bioactivities of Rumex crispus L. leaves and root extracts using toxicity, antimicrobial, and antiparasitic assays. Evid Based Complement Alternat Med 2019:1–13. https://doi.org/10.1155/2019/6825297
Jain V, Yogavel M, Kikuchi H, Oshima Y, Hariguchi N, Matsumoto M, Goel P, Touquet B, Jumani RS, Tacchini-Cottier F, Harlos K, Huston CD, Hakimi M-A, Sharma A (2017) Targeting prolyl-tRNA synthetase to accelerate drug discovery against malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis, and coccidiosis. Structure 25:1495–1505. https://doi.org/10.1016/j.str.2017.07.015
Jorgensen WL, Tirado-Rives J (1988) The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin. J Am Chem Soc 110:1657–1666. https://doi.org/10.1021/ja00214a001
Larayetan R, Ololade ZS, Ogunmola OO, Ladokun A (2019) Phytochemical constituents, antioxidant, cytotoxicity, antimicrobial, antitrypanosomal, and antimalarial potentials of the crude extracts of Callistemon citrinus. Evid Based Complement Alternat Med 2019:1–14. https://doi.org/10.1155/2019/5410923
Madhavi Sastry G, Adzhigirey M, Day T, Annabhimoju R, Sherman W (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27:221–234. https://doi.org/10.1007/s10822-013-9644-8
Manickam Y, Chaturvedi R, Babbar P, Malhotra N, Jain V, Sharma A (2018) Drug targeting of one or more aminoacyl-tRNA synthetase in the malaria parasite Plasmodium falciparum. Drug Discov Today 23:1233–1240. https://doi.org/10.1016/j.drudis.2018.01.050
McBride WG (1977) Thalidomide embryopathy. Teratology 16:79–82. https://doi.org/10.1002/tera.1420160113
Mishra BB, Tiwari VK (2011) Natural products: an evolving role in future drug discovery. Eur J Med Chem 46:4769–4807. https://doi.org/10.1016/j.ejmech.2011.07.057
Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335. https://doi.org/10.1021/np200906s
Ning YM, Gulley JL (2010) Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. https://www.ncbi.nlm.nih.gov/pubmed/20308663. Accessed 8 Jan 2019
Novoa EM, Camacho N, Tor A, Wilkinson B, Moss S, Marín-García P, Azcárate IG, Bautista JM, Mirando AC, Francklyn CS, Varon S, Royo M, Cortés A, Ribas de Pouplana L (2014) Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo. Proc Natl Acad Sci USA 111:E5508–5517. https://doi.org/10.1073/pnas.1405994111
Pammolli F, Magazzini L, Riccaboni M (2011) The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov 10:428–438. https://doi.org/10.1038/nrd3405
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612. https://doi.org/10.1002/jcc.20084
Pham JS, Dawson KL, Jackson KE, Lim EE, Pasaje CFA, Turner KEC, Ralph SA (2014) Aminoacyl-tRNA synthetases as drug targets in eukaryotic parasites. Int J Parasitol Drugs Drug Resist 4:1–13. https://doi.org/10.1016/j.ijpddr.2013.10.001
Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M (2019) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18:41–58. https://doi.org/10.1038/nrd.2018.168
Rusch M, Thevenon A, Hoepfner D, Aust T, Studer C, Patoor M, Rollin P, Livendahl M, Ranieri B, Schmitt E, Spanka C, Gademann K, Bouchez LC (2019) Design and synthesis of metabolically stable tRNA synthetase inhibitors derived from cladosporin. Chembiochem Eur J Chem Biol 20:644–649. https://doi.org/10.1002/cbic.201800587
Sajish M, Schimmel P (2014) A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 519:370–373. https://doi.org/10.2210/pdb4qbt/pdb
Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815. https://doi.org/10.1006/jmbi.1993.1626
Shim JS, Liu JO (2014) Recent advances in drug repositioning for the discovery of new anticancer drugs. Int J Biol Sci 10:654–663. https://doi.org/10.7150/ijbs.9224
Uzor PF (2020) Alkaloids from plants with antimalarial activity: a review of recent studies. Evid Based Complement Alternat Med 2020:1–17. https://doi.org/10.1155/2020/8749083
Wang J, Xu C, Wong YK, Li Y, Liao F, Jiang T, Tu Y (2019) Artemisinin, the magic drug discovered from traditional chinese medicine. Engineering 5:32–39. https://doi.org/10.1016/j.eng.2018.11.011
Wells TNC (2011) Natural products as starting points for future anti-malarial therapies: going back to our roots? Malar J 10(Suppl 1):S3. https://doi.org/10.1186/1475-2875-10-S1-S3
Widyawaruyanti A, Harwiningtias N, Tumewu L, Hafid AF, Soetjipto, (2020) Effect of formulated Artocarpus champeden extract on parasite growth and immune response of Plasmodium berghei —infected mice. Evid Based Complement Alternat Med 2020:1–7. https://doi.org/10.1155/2020/4678634
Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J (2006) DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res 34:D668–672. https://doi.org/10.1093/nar/gkj067
World malaria report (2019) https://www.who.int/publications-detail/world-malaria-report-2019. Accessed Jan 18 2020
Zeng X, Zhang P, He W, Qin C, Chen S, Tao L, Wang Y, Tan Y, Gao D, Wang B, Chen Z, Chen W, Jiang YY, Chen YZ (2018) NPASS: natural product activity and species source database for natural product research, discovery and tool development. Nucleic Acids Res 46:D1217–D1222. https://doi.org/10.1093/nar/gkx1026
Acknowledgements
The authors would like to thank Maitri Jain for setting up docking calculation for the prolyl-tRNA synthetases. Support and encouragement by the Ahmedabad University fraternity is duly acknowledged.
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MD ideated the study and designed the methodology. KD and NP performed the experiments. MD, KD, and NP analyzed the results and prepared the figures. KD and NP prepared a draft for the manuscript which was substantially revised by MD. All the authors approve the submitted manuscript.
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Doshi, K., Pandya, N. & Datt, M. In silico assessment of natural products and approved drugs as potential inhibitory scaffolds targeting aminoacyl-tRNA synthetases from Plasmodium. 3 Biotech 10, 470 (2020). https://doi.org/10.1007/s13205-020-02460-6
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DOI: https://doi.org/10.1007/s13205-020-02460-6