Bui Thi Buu Hue * , Cuong Quoc Nguyen and Quang De Tran

* Corresponding author (btbhue@ctu.edu.vn)

Main Article Content


Aminoacyl-tRNA synthetases (aaRSs) are one of the leading targets for the development of antibiotic agents. In this paper, we reported the discovery of aaRS inhibitors using a structure-based virtual screening method. The interactions of 52 designed structures with the methionyl-tRNA synthetase (MetRS) target were performed by docking the ligands into the active zone of the MetRS using Autodock Vina. The data revealed 14 compounds displaying interactions with key amino acids (Asp287, Tyr250, Val473, Trp474, Phe522, Ile519, Ala477, Leu478, and His523) at the binding pocket of the enzyme, indicating their potential as MetRS inhibitors. These results could be served as the references for further synthetic work and bioassays experiments for discovering MetRS inhibitors and other pharmaceutical agents that may assist in the generation of new antibiotics.

Keywords: Aminoacyl-tRNA synthetase, inhibitor, antibiotics, docking, virtual screening, structure-based drug design

Article Details


Barbuceanu, S. F, Bancescu, G., Cretu, O. D., Draghici, C., Bancescu, A., Radu-Popescu M. (2010). New heterocyclic compounds from 1,3,4-thiadiazole, 1,3,4-oxadiazole and 1,2,4-triazole class with potential antibacterial activity. Revista de Chimie (Bucharest), 61(2), 140–145.

Bender, A., & Glen, R. C. (2005). A Discussion of Measures of Enrichment in Virtual Screening: Comparing the Information Content of Descriptors with Increasing Levels of Sophistication. Journal of Chemical Information and Modeling, 45(5), 1369–1375. https://doi.org/10.1021/ci0500177

Bissantz, C., Folkers, G., & Rognan, D. (2000). Protein-Based Virtual Screening of Chemical Databases. 1. Evaluation of Different Docking/Scoring Combinations. Journal of Medicinal Chemistry, 43(25), 4759–4767. https://doi.org/10.1021/jm001044l

Bouz, G., & Zitko, J. (2021). Inhibitors of aminoacyl-tRNA synthetases as antimycobacterial compounds: An up-to-date review. Bioorganic Chemistry, 110, 104806. https://doi.org/10.1016/j.bioorg.2021.104806

Buckner, F. S., Ranade, R. M., Gillespie, J. R., Shibata, S., Hulverson, M. A., Zhang, Z., Huang, W., Choi, R., Verlinde, C. L. M. J., Hol, W. G. J., Ochida, A., Akao, Y., Choy, R. K. M., Van Voorhis, W. C., Arnold, S. L. M., Jumani, R. S., Huston, C. D., & Fan, E. (2019). Optimization of Methionyl tRNA-Synthetase Inhibitors for Treatment of Cryptosporidium Infection. Antimicrobial Agents and Chemotherapy, 63(4), e02061-18. https://doi.org/10.1128/AAC.02061-18

Bui, H. T. B., Nguyen, P. H., Pham, Q. M., Tran, H. P., Tran, D. Q., Jung, H., Hong, Q. V., Nguyen, Q. C., Nguyen, Q. P., Le, H. T., & Yang, S.-G. (2022). Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety. Molecules, 27(7), 2204. https://doi.org/10.3390/molecules27072204

Bui, H. T. B., Do, K. M., Nguyen, H. T. D., Mai, H. V., Danh, T. L. D., Tran, D. Q., & Morita, H. (2021). Efficient one-pot tandem synthesis and cytotoxicity evaluation of 2,3-disubstituted quinazolin-4(3H)-one derivatives. Tetrahedron, 98, 132426. https://doi.org/10.1016/j.tet.2021.132426

Bui Thi Buu Hue, Hien Minh Nguyen, Mai Van Hieu, Danh La Duc Thanh, Nguyen Hoang Son, Tran Quang De, and Hiroyuki Morita (2019). Facile sodium metabisulfite mediated synthesis of 1,2-disubstituted benzimidazoles and cytotoxicity evaluation, Heterocycles, Vol. 98, No. 5, 650-665.

Critchley, I. A., Green, L. S., Young, C. L., Bullard, J. M., Evans, R. J., Price, M., Jarvis, T. C., Guiles, J. W., Janjic, N., & Ochsner, U. A. (2009). Spectrum of activity and mode of action of REP3123, a new antibiotic to treat Clostridium difficile infections. Journal of Antimicrobial Chemotherapy, 63(5), 954–963. https://doi.org/10.1093/jac/dkp041

Critchley, I. A., Young, C. L., Stone, K. C., Ochsner, U. A., Guiles, J., Tarasow, T., & Janjic, N. (2005). Antibacterial Activity of REP8839, a New Antibiotic for Topical Use. Antimicrobial Agents and Chemotherapy, 49(10), 4247–4252. https://doi.org/10.1128/AAC.49.10.4247-4252.2005

Dallakyan, S., & Olson, A. J. (2015). Small-Molecule Library Screening by Docking with PyRx. In J. E. Hempel, C. H. Williams, & C. C. Hong (Eds.), Chemical Biology: Methods and Protocols (pp. 243–250). Springer. https://doi.org/10.1007/978-1-4939-2269-7_19.

Desai N, Bhatt N, Somani H, Trivedi A. (2013). Synthesis, antimicrobial and cytotoxic activities of some novel thiazole clubbed 1,3,4-oxadiazoles. Eur. J. Med. Chem. 67, 54–59.

Devine, W. G., Diaz-Gonzalez, R., Ceballos-Perez, G., Rojas, D., Satoh, T., Tear, W., Ranade, R. M., Barros-Álvarez, X., Hol, W. G. J., Buckner, F. S., Navarro, M., & Pollastri, M. P. (2017). From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis. ACS Infectious Diseases, 3(3), 225–236. https://doi.org/10.1021/acsinfecdis.6b00202

Friesner, R. A., Banks, J. L., Murphy, R. B., Halgren, T. A., Klicic, J. J., Mainz, D. T., Repasky, M. P., Knoll, E. H., Shelley, M., Perry, J. K., Shaw, D. E., Francis, P., & Shenkin, P. S. (2004). Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. Journal of Medicinal Chemistry, 47(7), 1739–1749. https://doi.org/10.1021/jm0306430

Frisch, M., Trucks, G., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., Barone, V., Mennucci, B., & Petersson, Ga. (2009). gaussian 09, Revision d. 01, Gaussian. Inc., Wallingford CT, 201.

Grosdidier, A., Zoete, V., & Michielin, O. (2011). SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Research, 39(suppl_2), W270–W277. https://doi.org/10.1093/nar/gkr366.

Guimaraes C.R.W., Boger D.L., Jorgensen W.L. (2005). Elucidation of fatty acid amide hydrolase inhibition by potent α-ketoheterocycle derivatives from Monte Carlo simulations. J. Am. Chem. Soc. 127(49), 17377–17384.

Huang, W., Zhang, Z., Barros-Álvarez, X., Koh, C. Y., Ranade, R. M., Gillespie, J. R., Creason, S. A., Shibata, S., Verlinde, C. L. M. J., Hol, W. G. J., Buckner, F. S., & Fan, E. (2016). Structure-guided design of novel Trypanosoma brucei Methionyl-tRNA synthetase inhibitors. European Journal of Medicinal Chemistry, 124, 1081–1092. https://doi.org/10.1016/j.ejmech.2016.10.024

Hue, B. T. B., Nguyen, P. H., De, T. Q., Van Hieu, M., Jo, E., Van Tuan, N., Thoa, T. T., Anh, L. D., Son, N. H., La Duc Thanh, D., Dupont-Rouzeyrol, M., Grailhe, R., & Windisch, M. P. (2020). Benzimidazole Derivatives as Novel Zika Virus Inhibitors. ChemMedChem, 15(15), 1453–1463. https://doi.org/10.1002/cmdc.202000124

Hussain, T., Yogavel, M., & Sharma, A. (2015). Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases. Antimicrobial Agents and Chemotherapy, 59(4), 1856–1867. https://doi.org/10.1128/AAC.02220-13

Jones, G., Willett, P., Glen, R. C., Leach, A. R., & Taylor, R. (1997). Development and validation of a genetic algorithm for flexible docking11Edited by F. E. Cohen. Journal of Molecular Biology, 267(3), 727–748. https://doi.org/10.1006/jmbi.1996.0897

Kitchen, D. B., Decornez, H., Furr, J. R., & Bajorath, J. (2004). Docking and scoring in virtual screening for drug discovery: Methods and applications. Nature Reviews Drug Discovery, 3(11), 935–949. https://doi.org/10.1038/nrd1549

Koh, C. Y., Kim, J. E., Shibata, S., Ranade, R. M., Yu, M., Liu, J., Gillespie, J. R., Buckner, F. S., Verlinde, C. L. M. J., Fan, E., & Hol, W. G. J. (2012). Distinct states of methionyl-tRNA synthetase indicate inhibitor binding by conformational selection. Structure (London, England: 1993), 20(10), 1681–1691. https://doi.org/10.1016/j.str.2012.07.011

Kovalenko, O. P., Volynets, G. P., Rybak, M. Y., Starosyla, S. A., Gudzera, O. I., Lukashov, S. S., Bdzhola, V. G., Yarmoluk, S. M., Boshoff, H. I., & Tukalo, M. A. (2019). Dual-target inhibitors of mycobacterial aminoacyl-tRNA synthetases among N-benzylidene-N′-thiazol-2-yl-hydrazines. MedChemComm, 10(12), 2161–2169. https://doi.org/10.1039/C9MD00347A.

Kumar GS, Rajendraprasad Y, Mallikarjuna B, Chandrashekar S, Kistayya C. (2010). Synthesis of some novel 2-substituted-5-[isopropylthiazole] clubbed 1,2,4-triazole and 1,3,4-oxadiazoles as potential antimicrobial and antitubercular agents. Eur. J. Med. Chem. 45(5), 2063–2074.

Lomeli, B. K., Galbraith, H., Schettler, J., Saviolakis, G. A., El-Amin, W., Osborn, B., Ravel, J., Hazleton, K., Lozupone, C. A., Evans, R. J., Bell, S. J., Ochsner, U. A., Jarvis, T. C., Baqar, S., & Janjic, N. (2019). Multiple-Ascending-Dose Phase 1 Clinical Study of the Safety, Tolerability, and Pharmacokinetics of CRS3123, a Narrow-Spectrum Agent with Minimal Disruption of Normal Gut Microbiota. Antimicrobial Agents and Chemotherapy, 64(1), e01395-19. https://doi.org/10.1128/AAC.01395-19.

Maria M. (2021). Synthesis of Antimicrobial Benzimidazole–Pyrazole Compounds and Their Biological Activities. Antibiotics, 10(8), 1002; https://doi.org/10.3390/antibiotics10081002

Nayak, S. U., Griffiss, J. M., Blumer, J., O’Riordan, M. A., Gray, W., McKenzie, R., Jurao, R. A., An, A. T., Le, M., Bell, S. J., Ochsner, U. A., Jarvis, T. C., Janjic, N., & Zenilman, J. M. (2017). Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study. Antimicrobial Agents and Chemotherapy, 61(8), e02760-16. https://doi.org/10.1128/AAC.02760-16

Nguyen, N. T., Nguyen, T. H., Pham, T. N. H., Huy, N. T., Bay, M. V., Pham, M. Q., Nam, P. C., Vu, V. V., & Ngo, S. T. (2020). Autodock Vina Adopts More Accurate Binding Poses but Autodock4 Forms Better Binding Affinity. Journal of Chemical Information and Modeling, 60(1), 204–211. https://doi.org/10.1021/acs.jcim.9b00778

Ojo, K. K., Ranade, R. M., Zhang, Z., Dranow, D. M., Myers, J. B., Choi, R., Hewitt, S. N., Edwards, T. E., Davies, D. R., Lorimer, D., Boyle, S. M., Barrett, L. K., Buckner, F. S., Fan, E., & Voorhis, W. C. V. (2016). Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis. PLOS ONE, 11(8), e0160350. https://doi.org/10.1371/journal.pone.0160350

Duckworth, B.P., M. Nelson, K., & C. Aldrich, C. (2012). Adenylating Enzymes in Mycobacterium tuberculosis as Drug Targets. Current Topics in Medicinal Chemistry, 12(7), 766–796.

Schneidman-Duhovny, D., Inbar, Y., Nussinov, R., & Wolfson, H. J. (2005). PatchDock and SymmDock: Servers for rigid and symmetric docking. Nucleic Acids Research, 33(suppl_2), W363–W367. https://doi.org/10.1093/nar/gki481

Shibata, S., Gillespie, J. R., Kelley, A. M., Napuli, A. J., Zhang, Z., Kovzun, K. V., Pefley, R. M., Lam, J., Zucker, F. H., Van Voorhis, W. C., Merritt, E. A., Hol, W. G. J., Verlinde, C. L. M. J., Fan, E., & Buckner, F. S. (2011). Selective Inhibitors of Methionyl-tRNA Synthetase Have Potent Activity against Trypanosoma brucei Infection in Mice. Antimicrobial Agents and Chemotherapy, 55(5), 1982–1989. https://doi.org/10.1128/AAC.01796-10

Shibata, S., Gillespie, J. R., Ranade, R. M., Koh, C. Y., Kim, J. E., Laydbak, J. U., Zucker, F. H., Hol, W. G. J., Verlinde, C. L. M. J., Buckner, F. S., & Fan, E. (2012). Urea-Based Inhibitors of Trypanosoma brucei Methionyl-tRNA Synthetase: Selectivity and in Vivo Characterization. Journal of Medicinal Chemistry, 55(14), 6342–6351. https://doi.org/10.1021/jm300303e.

Schultes, S., de Graaf, C., Haaksma, E. E., de Esch, I. J., Leurs, R., & Krämer, O. (2010). Ligand efficiency as a guide in fragment hit selection and optimization. Drug Discovery Today: Technologies, 7(3), e157-e162.

Reddy, A. S., Pati, S. P., Kumar, P. P, Pradeep, H. N. & Sastry, N. R. (2007). Virtual Screening in Drug Discovery—A Computational Perspective. Current Protein and Peptide Science, 8(4), 329–351. https://doi.org/10.2174/138920307781369427.

Tahlan, S., Kumar, S. & Narasimhan, B. (2019). Antimicrobial potential of 1H-benzo[d]imidazole scaffold: a review, BMC Chemistry 13, 18. https://doi.org/10.1186/s13065-019-0521-y

Teresa G. and Piotr Ś. (2021). Antimicrobial Activity of 1,3,4-Oxadiazole Derivatives, Int. J. Mol. Sci., 22, 6979.

Torrie, L. S., Brand, S., Robinson, D. A., Ko, E. J., Stojanovski, L., Simeons, F. R. C., Wyllie, S., Thomas, J., Ellis, L., Osuna-Cabello, M., Epemolu, O., Nühs, A., Riley, J., MacLean, L., Manthri, S., Read, K. D., Gilbert, I. H., Fairlamb, A. H., & De Rycker, M. (2017). Chemical Validation of Methionyl-tRNA Synthetase as a Druggable Target in Leishmania donovani. ACS Infectious Diseases, 3(10), 718–727. https://doi.org/10.1021/acsinfecdis.7b00047

Trott, O., & Olson, A. J. (2010). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), 455–461. https://doi.org/10.1002/jcc.21334

Willett, P., Barnard, J. M., & Downs, G. M. (1998). Chemical Similarity Searching. Journal of Chemical Information and Computer Sciences, 38(6), 983–996. https://doi.org/10.1021/ci9800211

Zhang, Z., Barros-Álvarez, X., Gillespie, J. R., Ranade, R. M., Huang, W., Shibata, S., Molasky, N. M. R., Faghih, O., Mushtaq, A., Choy, R. K. M., Hostos, E. de, Hol, W. G. J., Verlinde, C. L. M. J., Buckner, F. S., & Fan, E. (2020). Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei. RSC Medicinal Chemistry, 11(8), 885–895. https://doi.org/10.1039/D0MD00057D

Zhang, Z., Koh, C. Y., Ranade, R. M., Shibata, S., Gillespie, J. R., Hulverson, M. A., Huang, W., Nguyen, J., Pendem, N., Gelb, M. H., Verlinde, C. L. M. J., Hol, W. G. J., Buckner, F. S., & Fan, E. (2016). 5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors. ACS Infectious Diseases, 2(6), 399–404. https://doi.org/10.1021/acsinfecdis.6b00036.

Zhaojun Z., Qingzhong L., Wooseong K., Nagendran T., Beth B. F., Eleftherios M. (2018). Antimicrobial activity of 1,3,4-oxadiazole derivatives against planktonic cells and biofilm of Staphylococcus aureus. Future Med Chem, 10(3), 283-296.

Most read articles by the same author(s)