In silico Identification of Potential Inhibitors against Staphylococcus aureus Tyrosyl-tRNA Synthetase
- Authors: Monobe K.1, Taniguchi H.1, Aoki S.1
-
Affiliations:
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology
- Issue: Vol 20, No 5 (2024)
- Pages: 452-462
- Section: Chemistry
- URL: https://rjeid.com/1573-4099/article/view/644092
- DOI: https://doi.org/10.2174/1573409919666230612120819
- ID: 644092
Cite item
Full Text
Abstract
Background:Drug-resistant Staphylococcus aureus (S. aureus) has spread from nosocomial to community-acquired infections. Novel antimicrobial drugs that are effective against resistant strains should be developed. S. aureus tyrosyl-tRNA synthetase (saTyrRS) is considered essential for bacterial survival and is an attractive target for drug screening.
Objective:The purpose of this study was to identify potential new inhibitors of saTyrRS by screening compounds in silico and evaluating them using molecular dynamics (MD) simulations.
Methods:A 3D structural library of 154,118 compounds was screened using the DOCK and GOLD docking simulations and short-time MD simulations. The selected compounds were subjected to MD simulations of a 75-ns time frame using GROMACS..
Results:Thirty compounds were selected by hierarchical docking simulations. The binding of these compounds to saTyrRS was assessed by short-time MD simulations. Two compounds with an average value of less than 0.15 nm for the ligand RMSD were ultimately selected. The longtime (75 ns) MD simulation results demonstrated that two novel compounds bound stably to saTyrRS in silico.
Conclusion:Two novel potential saTyrRS inhibitors with different skeletons were identified by in silico drug screening using MD simulations. The in vitro validation of the inhibitory effect of these compounds on enzyme activity and their antibacterial effect on drug-resistant S. aureus would be useful for developing novel antibiotics.
About the authors
Kohei Monobe
Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology
Email: info@benthamscience.net
Hinata Taniguchi
Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology
Email: info@benthamscience.net
Shunsuke Aoki
Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology
Author for correspondence.
Email: info@benthamscience.net
References
- Cheung, GYC; Bae, JS; Otto, M. Pathogenicity and virulence of Staphylococcus aureus. Virulence., 2021, 12(1), 547. doi: 10.1080/21505594.2021.1878688
- Kluytmans, J.A.J.W.; Wertheim, H.F.L. Nasal carriage of Staphylococcus aureus and prevention of nosocomial infections. Infection, 2005, 33(1), 3-8. doi: 10.1007/s15010-005-4012-9 PMID: 15750752
- Lakhundi, S; Zhang, K. Methicillin-resistant Staphylococcus aureus: Molecular characterization, evolution, and epidemiology. Clin. Microbiol. Rev., 2018, 31(4), e00020-e00028.
- McGuinness, WA; Malachowa, N; DeLeo, FR Focus: Infectious diseases: Vancomycin resistance in Staphylococcus aureus. Yale J. Biol. Med., 2017, 90(2), 269.
- Otto, M. community-associated MRSA: What makes them special? Int. J. Med. Microbiol., 2013, 303(0), 324.
- Balakirski, G.; Hischebeth, G.; Altengarten, J.; Exner, D.; Bieber, T.; Dohmen, J.; Engelhart, S. Recurrent mucocutaneous infections caused by PVL‐positive Staphylococcus aureus strains: A challenge in clinical practice. J. Dtsch. Dermatol. Ges., 2020, 18(4), 315-322. doi: 10.1111/ddg.14058 PMID: 32196137
- Deurenberg, R.H.; Stobberingh, E.E. The evolution of Staphylococcus aureus. Infect. Genet. Evol., 2008, 8(6), 747-763. doi: 10.1016/j.meegid.2008.07.007 PMID: 18718557
- Toner, E.; Adalja, A.; Gronvall, GK; Cicero, A.; Inglesby, V.TV Antimicrobial resistance is a global health emergency. Health Secur., 2015, 13(3), 153.
- Lee Ventola, C. The antibiotic resistance crisis: Part 2: Management strategies and new agents. Pharm Ther., 2015, 40(5), 344.
- WHO. global priority pathogens list of antibiotic-resistant bacteria, Available from: https://www.doherty.edu.au/news-events/news/who-global-priority-pathogens-list-of-antibiotic-resistant-bacteria
- Facts about antibiotic resistance. Available from: https://www.idsociety.org/public-health/antimicrobial-resistance/archive-antimicrobial-resistance/facts-about-antibiotic-resistance/
- Bouz, G.; Zitko, J. Inhibitors of aminoacyl-tRNA synthetases as antimycobacterial compounds: An up-to-date review. Bioorg. Chem., 2021, 110, 104806. doi: 10.1016/j.bioorg.2021.104806 PMID: 33799176
- Skupińska, M.; Stȩpniak, P.; Łȩtowska, I.; Rychlewski, L.; Barciszewska, M.; Barciszewski, J. Natural compounds as inhibitors of tyrosyl-tRNA synthetase. Microb Drug Resist., 2017, 23(3), 308. doi: 10.1089/mdr.2015.0272
- Xiao, Z.P.; Ma, T.W.; Liao, M.L.; Feng, Y.T.; Peng, X.C.; Li, J.L.; Li, Z.P.; Wu, Y.; Luo, Q.; Deng, Y.; Liang, X.; Zhu, H.L. Tyrosyl-tRNA synthetase inhibitors as antibacterial agents: Synthesis, molecular docking and structureactivity relationship analysis of 3-aryl-4-arylaminofuran-2(5H)-ones. Eur. J. Med. Chem., 2011, 46(10), 4904-4914. doi: 10.1016/j.ejmech.2011.07.047 PMID: 21856050
- Brown, P.; Eggleston, D.S.; Haltiwanger, R.C.; Jarvest, R.L.; Mensah, L.; OHanlon, P.J.; Pope, A.J. Synthetic analogues of SB-219383. Novel C-glycosyl peptides as inhibitors of tyrosyl tRNA synthetase. Bioorg. Med. Chem. Lett., 2001, 11(5), 711-714. doi: 10.1016/S0960-894X(01)00039-7 PMID: 11266175
- Qiu, X; Janson, CA; Smith, WW; Green, SM; McDevitt, P; Johanson, K Crystal structure of Staphylococcus aureus tyrosyl-tRNA synthetase in complex with a class of potent and specific inhibitors. Protein Sci., 2008, 10(10), 2008.
- Li, T.; Froeyen, M.; Herdewijn, P. Comparative structural dynamics of Tyrosyl-tRNA synthetase complexed with different substrates explored by molecular dynamics. Eur. Biophys. J., 2008, 38(1), 25-35. doi: 10.1007/s00249-008-0350-8 PMID: 18560823
- Greenwood, R.C.; Gentry, D.R. Confirmation of the antibacterial mode of action of SB-219383, a novel tyrosyl tRNA synthetase inhibitor from a Micromonospora sp. J. Antibiot., 2002, 55(4), 423-426. doi: 10.7164/antibiotics.55.423 PMID: 12061551
- ChemBridge, Home. Available from: https://www.chembridge.com/
- Molecular operating environment (MOE) ⋅ MOEsaic.. PSILO, Available from: https://www.chemcomp.com/Products.htm
- Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235.
- Lang, PT; Brozell, SR; Mukherjee, S; Pettersen, EF; Meng, EC; Thomas, V DOCK 6: Combining techniques to model RNAsmall molecule complexes. RNA., 2009, 15(6), 1219.
- Jones, G.; Willett, P.; Glen, R.C.; Leach, A.R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking 1 1Edited by F. E. Cohen. J. Mol. Biol., 1997, 267(3), 727-748. doi: 10.1006/jmbi.1996.0897 PMID: 9126849
- Hollingsworth, SA; Dror, RO Molecular dynamics simulation for all. Neuron., 2018, 99(6), 1129. doi: 10.1016/j.neuron.2018.08.011
- Abraham, M.J.; Murtola, T.; Schulz, R.; Páll, S.; Smith, J.C.; Hess, B.; Lindahl, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 2015, 1-2, 19-25. doi: 10.1016/j.softx.2015.06.001
- Jo, S.; Kim, T.; Iyer, V.G.; Im, W. CHARMM-GUI: A web-based graphical user interface for CHARMM. J. Comput. Chem., 2008, 29(11), 1859-1865. doi: 10.1002/jcc.20945 PMID: 18351591
- Brooks, B.R.; Brooks, C.L., III; Mackerell, A.D., Jr; Nilsson, L.; Petrella, R.J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; Caflisch, A.; Caves, L.; Cui, Q.; Dinner, A.R.; Feig, M.; Fischer, S.; Gao, J.; Hodoscek, M.; Im, W.; Kuczera, K.; Lazaridis, T.; Ma, J.; Ovchinnikov, V.; Paci, E.; Pastor, R.W.; Post, C.B.; Pu, J.Z.; Schaefer, M.; Tidor, B.; Venable, R.M.; Woodcock, H.L.; Wu, X.; Yang, W.; York, D.M.; Karplus, M. CHARMM: The biomolecular simulation program. J. Comput. Chem., 2009, 30(10), 1545-1614. doi: 10.1002/jcc.21287 PMID: 19444816
- Lee, J.; Cheng, X.; Swails, J.M.; Yeom, M.S.; Eastman, P.K.; Lemkul, J.A.; Wei, S.; Buckner, J.; Jeong, J.C.; Qi, Y.; Jo, S.; Pande, V.S.; Case, D.A.; Brooks, C.L., III; MacKerell, A.D., Jr; Klauda, J.B.; Im, W. CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field. J. Chem. Theory Comput., 2016, 12(1), 405-413. doi: 10.1021/acs.jctc.5b00935 PMID: 26631602
- Hess, B.; Bekker, H.; Berendsen, H.J.C.; Fraaije, J.G.E.M. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem., 1997, 18(12), 1463-1472. doi: 10.1002/(SICI)1096-987X(199709)18:123.0.CO;2-H
- Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald: An N Ŋlog(N) method for Ewald sums in large systems. J. Chem. Phys., 1993, 98(12), 10089-10092. doi: 10.1063/1.464397
- Taira, J.; Murakami, K.; Monobe, K.; Kuriki, K.; Fujita, M.; Ochi, Y. Identification of novel inhibitors for mycobacterial polyketide synthase 13 via in silico drug screening assisted by the parallel compound screening with genetic algorithm-based programs. J Antibiot, 2022, 75(10), 552-558.
- Kuriki, K.; Matsumoto, R.; Ijichi, C.; Taira, J.; Aoki, S. Establishment of in silico prediction methods for potential bitter molecules using the human T2R14 homology-model structure. Chem. Biol. Lett., 2022, 9(3), 351.
- Miryala, S.K.; Basu, S.; Naha, A.; Debroy, R.; Ramaiah, S.; Anbarasu, A.; Natarajan, S. Identification of bioactive natural compounds as efficient inhibitors against Mycobacterium tuberculosis protein-targets: A molecular docking and molecular dynamics simulation study. J. Mol. Liq., 2021, 341, 117340. doi: 10.1016/j.molliq.2021.117340
- Karami, TK; Hailu, S; Feng, S; Graham, R; Gukasyan, HJ Eyes on Lipinskis rule of five: A new "rule of thumb" for physicochemical design space of ophthalmic drugs. J. Ocul. Pharmacol. Ther., 2022, 38(1), 43.
- Guterres, H; Im, W Improving protein-ligand docking results with high-throughput Molecular Dynamics simulations. J. Chem. Inf. Model., 2020, 60(4), 2189.
- Shehadi, IA; Abdelrahman, MT; Abdelraof, M; Rashdan, HRM Solvent-free synthesis, in vitro and in silico studies of novel potential 1,3,4-thiadiazole-based molecules against microbial pathogens. Molecules., 2022, 27(2), 342.
- Xiao, Z.P.; Wei, W.; Wang, P.F.; Shi, W.K.; Zhu, N.; Xie, M.Q.; Sun, Y.W.; Li, L.X.; Xie, Y.X.; Zhu, L.S.; Tang, N.; Ouyang, H.; Li, X.H.; Wang, G.C.; Zhu, H.L. Synthesis and evaluation of new tyrosyl-tRNA synthetase inhibitors as antibacterial agents based on a N2-(arylacetyl)glycinanilide scaffold. Eur. J. Med. Chem., 2015, 102, 631-638. doi: 10.1016/j.ejmech.2015.08.025 PMID: 26318069
- Wei, W.; Shi, W.K.; Wang, P.F.; Zeng, X.T.; Li, P.; Zhang, J.R.; Li, Q.; Tang, Z.P.; Peng, J.; Wu, L.Z.; Xie, M.Q.; Liu, C.; Li, X.H.; Wang, Y.C.; Xiao, Z.P.; Zhu, H.L. Adenosine analogs as inhibitors of tyrosyl-tRNA synthetase: Design, synthesis and antibacterial evaluation. Bioorg. Med. Chem., 2015, 23(20), 6602-6611. doi: 10.1016/j.bmc.2015.09.018 PMID: 26404408
- Adasme, M.F.; Linnemann, K.L.; Bolz, S.N.; Kaiser, F.; Salentin, S.; Haupt, V.J.; Schroeder, M. PLIP 2021: expanding the scope of the proteinligand interaction profiler to DNA and RNA. Nucleic Acids Res., 2021, 49(W1), W530-W534. doi: 10.1093/nar/gkab294 PMID: 33950214
- Poli, G; Granchi, C; Rizzolio, F; Tuccinardi, T. Application of MM-PBSA methods in virtual screening. Molecules, 2020, 25(8), 1971. doi: 10.3390/molecules25081971
- Valdés-Tresanco, M.S.; Valdés-Tresanco, M.E.; Valiente, P.A.; Moreno, E. Gmx_MMPBSA: A new tool to perform end-state free energy calculations with GROMACS. J. Chem. Theory Comput., 2021, 17(10), 6281-6291. doi: 10.1021/acs.jctc.1c00645 PMID: 34586825
- Miller, B.R., III; McGee, T.D., Jr; Swails, J.M.; Homeyer, N.; Gohlke, H.; Roitberg, A.E. MMPBSA.py: An efficient program for end-state free energy calculations. J. Chem. Theory Comput., 2012, 8(9), 3314-3321. doi: 10.1021/ct300418h PMID: 26605738
- Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717. doi: 10.1038/srep42717
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