Computational Insight into the Mechanism of Action of DNA Gyrase Inhibitors; Revealing a New Mechanism


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Abstract

Background:Discovery of novel antimicrobial agents is in need to deal with antibiotic resistance. Elucidating the mechanism of action for established drugs contributes to this endeavor. DNA gyrase is a therapeutic target used in the design and development of new antibacterial agents. Selective antibacterial gyrase inhibitors are available; however, resistance development against them is a big challenge. Hence, novel gyrase inhibitors with novel mechanisms are required.

Objective:The aim of this study is to elucidate mode of action for existing DNA gyrase inhibitors and to pave the way towards discovery of novel inhibitors.

Methods:In this study, the mechanism of action for selected DNA gyrase inhibitors available was carried out through molecular docking and molecular dynamics (MD) simulation. In addition, pharmacophore analysis, density functional theory (DFT) calculations, and computational pharmacokinetics analysis of the gyrase inhibitors were performed.

Results:This study demonstrated that all the DNA gyrase inhibitors investigated, except compound 14, exhibit their activity by inhibiting gyrase B at a binding pocket. The interaction of the inhibitors at Lys103 was found to be essential for the binding. The molecular docking and MD simulation results revealed that compound 14 could act by inhibiting gyrase A. A pharmacophore model that consisted of the features that would help the inhibition effect was generated. The DFT analysis demonstrated 14 had relatively high chemical stability. Computational pharmacokinetics analysis revealed that most of the explored inhibitors were estimated to have good drug-like properties. Furthermore, most of the inhibitors were found to be non-mutagenic.

Conclusion:In this study, mode of action elucidation through molecular docking and MD simulation, pharmacophore model generation, pharmacokinetic property prediction, and DFT study for selected DNA gyrase inhibitors were carried out. The outcomes of this study are anticipated to contribute to the design of novel gyrase inhibitors.

About the authors

Muhammed Muhammed

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Süleyman Demirel University

Author for correspondence.
Email: info@benthamscience.net

Esin Aki-Yalcin

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cyprus Health and Social Sciences University

Email: info@benthamscience.net

References

  1. Arandjelovic, P.; Doerflinger, M.; Pellegrini, M. Current and emerging therapies to combat persistent intracellular pathogens. Curr. Opin. Pharmacol., 2019, 48, 33-39. doi: 10.1016/j.coph.2019.03.013 PMID: 31051429
  2. Xu, Z.; Xu, D.; Zhou, W.; Zhang, X. Therapeutic potential of naturally occurring benzofuran derivatives and hybrids of benzofurans with other pharmacophores as antibacterial agents. Curr. Top. Med. Chem., 2022, 22(1), 64-82. doi: 10.2174/1568026621666211122162439 PMID: 34809548
  3. Yilmaz, S.; Yalcin, I.; Okten, S.; Onurdag, F.K.; Aki-Yalcin, E. Synthesis and investigation of binding interactions of 1,4-benzoxazine derivatives on topoisomerase IV in Acinetobacter baumannii. SAR QSAR Environ. Res., 2017, 28(11), 941-956. doi: 10.1080/1062936X.2017.1404490 PMID: 29206501
  4. Ebenezer, O.; Singh-Pillay, A.; Koorbanally, N.A.; Singh, P. Antibacterial evaluation and molecular docking studies of pyrazole–thiosemicarbazones and their pyrazole–thiazolidinone conjugates. Mol. Divers., 2021, 25(1), 191-204. doi: 10.1007/s11030-020-10046-w PMID: 32086698
  5. Pacios, O.; Blasco, L.; Bleriot, I.; Fernandez-Garcia, L.; González Bardanca, M.; Ambroa, A.; López, M.; Bou, G.; Tomás, M. Strategies to combat multidrug-resistant and persistent infectious diseases. Antibiotics, 2020, 9(2), 65. doi: 10.3390/antibiotics9020065 PMID: 32041137
  6. Qin, Y.; Xu, L.; Teng, Y.; Wang, Y.; Ma, P. Discovery of novel antibacterial agents: Recent developments in D‐alanyl‐D‐alanine ligase inhibitors. Chem. Biol. Drug Des., 2021, 98(3), 305-322. doi: 10.1111/cbdd.13899 PMID: 34047462
  7. Wise, R.; Blaser, M.; Carrs, O.; Cassell, G.; Fishman, N.; Guidos, R.; Levy, S.; Powers, J.; Norrby, R.; Tillotson, G.; Davies, R.; Projan, S.; Dawson, M.; Monnet, D.; Keogh-Brown, M.; Hand, K.; Garner, S.; Findlay, D.; Morel, C.; Wise, R.; Bax, R.; Burke, F.; Chopra, I.; Czaplewski, L.; Finch, R.; Livermore, D.; Piddock, L.J.V.; White, T. The urgent need for new antibacterial agents. J. Antimicrob. Chemother., 2011, 66(9), 1939-1940. doi: 10.1093/jac/dkr261 PMID: 21700627
  8. Mantravadi, P.; Kalesh, K.; Dobson, R.; Hudson, A.; Parthasarathy, A. The quest for novel antimicrobial compounds: Emerging trends in research, development, and technologies. Antibiotics, 2019, 8(1), 8. doi: 10.3390/antibiotics8010008 PMID: 30682820
  9. Collin, F.; Karkare, S.; Maxwell, A. Exploiting bacterial DNA gyrase as a drug target: Current state and perspectives. Appl. Microbiol. Biotechnol., 2011, 92(3), 479-497. doi: 10.1007/s00253-011-3557-z PMID: 21904817
  10. Schoeffler, A.J.; May, A.P.; Berger, J.M. A domain insertion in Escherichia coli GyrB adopts a novel fold that plays a critical role in gyrase function. Nucleic Acids Res., 2010, 38(21), 7830-7844. doi: 10.1093/nar/gkq665 PMID: 20675723
  11. Wang, J.C. Cellular roles of DNA topoisomerases: A molecular perspective. Nat. Rev. Mol. Cell Biol., 2002, 3(6), 430-440. doi: 10.1038/nrm831 PMID: 12042765
  12. Corbett, K.D.; Shultzaberger, R.K.; Berger, J.M. The C-terminal domain of DNA gyrase A adopts a DNA-bending β-pinwheel fold. Proc. Natl. Acad. Sci., 2004, 101(19), 7293-7298. doi: 10.1073/pnas.0401595101 PMID: 15123801
  13. Khan, T.; Sankhe, K.; Suvarna, V.; Sherje, A.; Patel, K.; Dravyakar, B. DNA gyrase inhibitors: Progress and synthesis of potent compounds as antibacterial agents. Biomed. Pharmacother., 2018, 103, 923-938. doi: 10.1016/j.biopha.2018.04.021 PMID: 29710509
  14. Hearnshaw, S.J.; Edwards, M.J.; Stevenson, C.E.; Lawson, D.M.; Maxwell, A. A new crystal structure of the bifunctional antibiotic simocyclinone D8 bound to DNA gyrase gives fresh insight into the mechanism of inhibition. J. Mol. Biol., 2014, 426(10), 2023-2033. doi: 10.1016/j.jmb.2014.02.017 PMID: 24594357
  15. Petrella, S.; Capton, E.; Raynal, B.; Giffard, C.; Thureau, A.; Bonneté, F.; Alzari, P.M.; Aubry, A.; Mayer, C. Overall structures of Mycobacterium tuberculosis DNA gyrase reveal the role of a corynebacteriales GyrB-specific insert in ATPase activity. Structure, 2019, 27(4), 579-589.e5. doi: 10.1016/j.str.2019.01.004 PMID: 30744994
  16. Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod., 2016, 79(3), 629-661. doi: 10.1021/acs.jnatprod.5b01055 PMID: 26852623
  17. Bush, N.G.; Diez-Santos, I.; Abbott, L.R.; Maxwell, A. Quinolones: Mechanism, lethality and their contributions to antibiotic resistance. Molecules, 2020, 25(23), 5662-5689. doi: 10.3390/molecules25235662 PMID: 33271787
  18. Blower, T.R.; Williamson, B.H.; Kerns, R.J.; Berger, J.M. Crystal structure and stability of gyrase–fluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proc. Natl. Acad. Sci., 2016, 113(7), 1706-1713. doi: 10.1073/pnas.1525047113 PMID: 26792525
  19. Bradford, P.A.; Miller, A.A.; O’Donnell, J.; Mueller, J.P. Zoliflodacin: An oral spiropyrimidinetrione antibiotic for the treatment of Neisseria gonorrheae, including multi-drug-resistant isolates. ACS Infect. Dis., 2020, 6(6), 1332-1345. doi: 10.1021/acsinfecdis.0c00021 PMID: 32329999
  20. Muhammed, M.T.; Aki-Yalcin, E. Pharmacophore modeling in drug discovery: Methodology and current status. J Turkish Chem Soc Sect. Chem, 2021, 8, 759-772.
  21. Muhammed, M.T.; Aki-Yalcin, E. Homology modeling in drug discovery: Overview, current applications, and future perspectives. Chem. Biol. Drug Des., 2019, 93(1), 12-20. doi: 10.1111/cbdd.13388 PMID: 30187647
  22. Muhammed, M.T. Son, Ç.D.; İzgü, F. Three dimensional structure prediction of panomycocin, a novel Exo-β-1,3-glucanase isolated from Wickerhamomyces anomalus NCYC 434 and the computational site-directed mutagenesis studies to enhance its thermal stability for therapeutic applications. Comput. Biol. Chem., 2019, 80, 270-277. doi: 10.1016/j.compbiolchem.2019.04.006 PMID: 31054539
  23. Fan, J.; Fu, A.; Zhang, L. Progress in molecular docking. Quant. Biol., 2019, 7(2), 83-89. doi: 10.1007/s40484-019-0172-y
  24. Muhammed, M.T.; Aki-Yalcin, E. Molecular docking: Principles, advances, and its applications in drug discovery. Lett. Drug Des. Discov., 2022, 19, 22. doi: 10.2174/1570180819666220922103109
  25. Kashid, B.B.; Ghanwat, A.A.; Khedkar, V.M.; Dongare, B.B.; Shaikh, M.H.; Deshpande, P.P.; Wakchaure, Y.B. Design, synthesis, in vitro antimicrobial, antioxidant evaluation, and molecular docking study of novel benzimidazole and benzoxazole derivatives. J. Heterocycl. Chem., 2019, 56(3), 895-908. doi: 10.1002/jhet.3467
  26. Alqahtani, S. In silico ADME-Tox modeling: Progress and prospects. Expert Opin. Drug Metab. Toxicol., 2017, 13(11), 1147-1158. doi: 10.1080/17425255.2017.1389897 PMID: 28988506
  27. Tretter, E.M.; Schoeffler, A.J.; Weisfield, S.R.; Berger, J.M. Crystal structure of the DNA gyrase GyrA N-terminal domain from Mycobacterium tuberculosis. Proteins, 2010, 78(2), 492-495. doi: 10.1002/prot.22600 PMID: 19787774
  28. Brvar, M.; Perdih, A.; Renko, M.; Anderluh, G.; Turk, D.; Solmajer, T. Structure-based discovery of substituted 4,5′-bithiazoles as novel DNA gyrase inhibitors. J. Med. Chem., 2012, 55(14), 6413-6426. doi: 10.1021/jm300395d PMID: 22731783
  29. Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res., 2021, 49(D1), D1388-D1395. doi: 10.1093/nar/gkaa971 PMID: 33151290
  30. Önem, E. Sarısu, H.C.; Özaydın, A.G.; Muhammed, M.T.; Ak, A. Phytochemical profile, antimicrobial, and anti‐quorum sensing properties of fruit stalks of Prunus avium L. Lett. Appl. Microbiol., 2021, 73(4), 426-437. doi: 10.1111/lam.13528 PMID: 34173244
  31. Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461. PMID: 19499576
  32. BIOVIA, Dassault Systèmes, Discovery Studio. Comprehensive modeling and simulating for life sciences.
  33. 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
  34. Schüttelkopf, A.W.; van Aalten, D.M.F. PRODRG: A tool for high-throughput crystallography of protein–ligand complexes. Acta Crystallogr. D Biol. Crystallogr., 2004, 60(8), 1355-1363. doi: 10.1107/S0907444904011679 PMID: 15272157
  35. Bjelkmar, P.; Larsson, P.; Cuendet, M.A.; Hess, B.; Lindahl, E. Implementation of the charmm force field in GROMACS: Analysis of protein stability effects from correction maps, virtual interaction sites, and water models. J. Chem. Theory Comput., 2010, 6(2), 459-466. doi: 10.1021/ct900549r PMID: 26617301
  36. Akkoc, S.; Karatas, H.; Muhammed, M.T.; Kökbudak, Z.; Ceylan, A.; Almalki, F.; Laaroussi, H.; Ben Hadda, T. Drug design of new therapeutic agents: Molecular docking, molecular dynamics simulation, DFT and POM analyses of new Schiff base ligands and impact of substituents on bioactivity of their potential antifungal pharmacophore site. J. Biomol. Struct. Dyn., 2022, 1-14. doi: 10.1080/07391102.2022.2111360 PMID: 35968554
  37. Accelrys Discovery Studio Client 3.5, Accelrys Software Inc., San Diego, CA.
  38. Gaussian 09, Revision B.01. Gaussian Inc., Wallingford.
  39. Becke, A.D. Density‐functional thermochemistry. IV. A new dynamical correlation functional and implications for exact‐exchange mixing. J. Chem. Phys., 1996, 104(3), 1040-1046. doi: 10.1063/1.470829
  40. Perdew, J.P.; Kurth, S.; Zupan, A.; Blaha, P. Accurate density functional with correct formal properties: A step beyond the generalized gradient approximation. Phys. Rev. Lett., 1999, 82(12), 2544-2547. doi: 10.1103/PhysRevLett.82.2544
  41. Dennington, R.D.; Keith, T.A.; Millam, J.M. GaussView 5.0; Gaussian Inc.: Wallingford, 2008, p. 20.
  42. 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(1), 42717. doi: 10.1038/srep42717 PMID: 28256516
  43. Han, Y.; Zhang, J.; Hu, C.Q.; Zhang, X.; Ma, B.; Zhang, P. In silico ADME and toxicity prediction of ceftazidime and its impurities. Front. Pharmacol., 2019, 10, 434-445. doi: 10.3389/fphar.2019.00434 PMID: 31068821
  44. Lafitte, D.; Lamour, V.; Tsvetkov, P.O.; Makarov, A.A.; Klich, M.; Deprez, P.; Moras, D.; Briand, C.; Gilli, R. DNA gyrase interaction with coumarin-based inhibitors: The role of the hydroxybenzoate isopentenyl moiety and the 5′-methyl group of the noviose. Biochemistry, 2002, 41(23), 7217-7223. doi: 10.1021/bi0159837 PMID: 12044152
  45. Holdgate, G.A.; Tunnicliffe, A.; Ward, W.H.J.; Weston, S.A.; Rosenbrock, G.; Barth, P.T.; Taylor, I.W.F.; Pauptit, R.A.; Timms, D. The entropic penalty of ordered water accounts for weaker binding of the antibiotic novobiocin to a resistant mutant of DNA gyrase: A thermodynamic and crystallographic study. Biochemistry, 1997, 36(32), 9663-9673. doi: 10.1021/bi970294+ PMID: 9245398
  46. Tian, W.; Chen, C.; Lei, X.; Zhao, J.; Liang, J. CASTp 3.0: Computed atlas of surface topography of proteins. Nucleic Acids Res., 2018, 46(W1), W363-W367. doi: 10.1093/nar/gky473 PMID: 29860391
  47. Taylor, S.N.; Marrazzo, J.; Batteiger, B.E.; Hook, E.W., III; Seña, A.C.; Long, J.; Wierzbicki, M.R.; Kwak, H.; Johnson, S.M.; Lawrence, K.; Mueller, J. Single-dose zoliflodacin (ETX0914) for treatment of urogenital gonorrhea. N. Engl. J. Med., 2018, 379(19), 1835-1845. doi: 10.1056/NEJMoa1706988 PMID: 30403954
  48. Basarab, G.S.; Kern, G.H.; McNulty, J.; Mueller, J.P.; Lawrence, K.; Vishwanathan, K.; Alm, R.A.; Barvian, K.; Doig, P.; Galullo, V.; Gardner, H.; Gowravaram, M.; Huband, M.; Kimzey, A.; Morningstar, M.; Kutschke, A.; Lahiri, S.D.; Perros, M.; Singh, R.; Schuck, V.J.A.; Tommasi, R.; Walkup, G.; Newman, J.V. Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases. Sci. Rep., 2015, 5(1), 11827. doi: 10.1038/srep11827
  49. Dong, Y.; Liao, M.; Meng, X.; Somero, G.N. Structural flexibility and protein adaptation to temperature: Molecular dynamics analysis of malate dehydrogenases of marine molluscs. Proc. Natl. Acad. Sci., 2018, 115(6), 1274-1279. doi: 10.1073/pnas.1718910115 PMID: 29358381
  50. Parr, R.G.; Donnelly, R.A.; Levy, M.; Palke, W.E. Electronegativity: The density functional viewpoint. J. Chem. Phys., 1978, 68(8), 3801-3807. doi: 10.1063/1.436185
  51. Chattaraj, P.K.; Sarkar, U.; Roy, D.R. Electrophilicity Index. Chem. Rev., 2006, 106(6), 2065-2091. doi: 10.1021/cr040109f PMID: 16771443
  52. Koopmans, T. About the assignment of wave functions and eigenvalues to the individual electrons of an atom. Physica, 1934, 1, 104-113. doi: 10.1016/S0031-8914(34)90011-2
  53. Miar, M.; Shiroudi, A.; Pourshamsian, K. Theoretical investigations on the HOMO–LUMO gap and global reactivity descriptor studies, natural bond orbital, and nucleus-independent chemical shifts analyses of 3-phenylbenzodthiazole-2(3H)-imine and its para-substituted derivatives: Solvent and subs. J. Chem. Res., 2021, 45, 147-158. doi: 10.1177/1747519820932091
  54. Ruiz-Morales, Y. HOMO-LUMO gap as an index of molecular size and structure for Polycyclic Aromatic Hydrocarbons (PAHs) and asphaltenes: A theoretical study. I. J. Phys. Chem. A, 2002, 106(46), 11283-11308. doi: 10.1021/jp021152e
  55. Han, M.İ.; Dengiz, C.; Doğan, Ş.D.; Gündüz, M.G.; Köprü, S.; Özkul, C. Isoquinolinedione-urea hybrids: Synthesis, antibacterial evaluation, drug-likeness, molecular docking and DFT studies. J. Mol. Struct., 2022, 1252, 132007. doi: 10.1016/j.molstruc.2021.132007
  56. Fonteh, P.; Elkhadir, A.; Omondi, B.; Guzei, I.; Darkwa, J.; Meyer, D. Impedance technology reveals correlations between cytotoxicity and lipophilicity of mono and bimetallic phosphine complexes. Biometals, 2015, 28(4), 653-667. doi: 10.1007/s10534-015-9851-y PMID: 25829148
  57. Barret, R. Importance and evaluation of the polar surface area (PSA and TPSA). In: Therapeutical Chemistry; , 2018; p. 89-95.
  58. Qidwai, T. QSAR modeling, docking and ADMET studies for exploration of potential anti-malarial compounds against Plasmodium falciparum. In Silico Pharmacol., 2017, 5(1), 6. doi: 10.1007/s40203-017-0026-0 PMID: 28726171
  59. Dahlgren, D.; Lennernäs, H. Intestinal permeability and drug absorption: Predictive experimental, computational and in vivo approaches. Pharmaceutics, 2019, 11(8), 411. Epub ahead of print doi: 10.3390/pharmaceutics11080411 PMID: 31412551
  60. Martin, Y.C. A bioavailability score. J. Med. Chem., 2005, 48(9), 3164-3170. doi: 10.1021/jm0492002 PMID: 15857122
  61. Muhammed, M.T.; Kuyucuklu, G.; Kaynak-Onurdag, F.; Aki-Yalcin, E. Synthesis, antimicrobial activity, and molecular modeling studies of some benzoxazole derivatives. Lett. Drug Des. Discov., 2022, 19(8), 757-768. doi: 10.2174/1570180819666220408133643
  62. Doherty, A.T.; Hayes, J.E.; Molloy, J.; Wood, C.; O’Donovan, M.R. Bone marrow micronucleus frequencies in the rat after oral administration of cyclophosphamide, hexamethylphosphoramide or gemifloxacin for 2 and 28 days. Toxicol. Res., 2013, 2(5), 321-327. doi: 10.1039/c3tx50028d

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