Computational Insight into the Mechanism of Action of DNA Gyrase Inhibitors; Revealing a New Mechanism
- Authors: Muhammed M.1, Aki-Yalcin E.2
-
Affiliations:
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Süleyman Demirel University
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cyprus Health and Social Sciences University
- Issue: Vol 20, No 3 (2024)
- Pages: 224-235
- Section: Chemistry
- URL: https://rjeid.com/1573-4099/article/view/643966
- DOI: https://doi.org/10.2174/1573409919666230419094700
- ID: 643966
Cite item
Full Text
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.
Keywords
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
- 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
- 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
- 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
- Ebenezer, O.; Singh-Pillay, A.; Koorbanally, N.A.; Singh, P. Antibacterial evaluation and molecular docking studies of pyrazolethiosemicarbazones and their pyrazolethiazolidinone conjugates. Mol. Divers., 2021, 25(1), 191-204. doi: 10.1007/s11030-020-10046-w PMID: 32086698
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Blower, T.R.; Williamson, B.H.; Kerns, R.J.; Berger, J.M. Crystal structure and stability of gyrasefluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proc. Natl. Acad. Sci., 2016, 113(7), 1706-1713. doi: 10.1073/pnas.1525047113 PMID: 26792525
- Bradford, P.A.; Miller, A.A.; ODonnell, 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
- 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.
- 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
- 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
- Fan, J.; Fu, A.; Zhang, L. Progress in molecular docking. Quant. Biol., 2019, 7(2), 83-89. doi: 10.1007/s40484-019-0172-y
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- BIOVIA, Dassault Systèmes, Discovery Studio. Comprehensive modeling and simulating for life sciences.
- 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
- Schüttelkopf, A.W.; van Aalten, D.M.F. PRODRG: A tool for high-throughput crystallography of proteinligand complexes. Acta Crystallogr. D Biol. Crystallogr., 2004, 60(8), 1355-1363. doi: 10.1107/S0907444904011679 PMID: 15272157
- 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
- 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
- Accelrys Discovery Studio Client 3.5, Accelrys Software Inc., San Diego, CA.
- Gaussian 09, Revision B.01. Gaussian Inc., Wallingford.
- 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
- 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
- Dennington, R.D.; Keith, T.A.; Millam, J.M. GaussView 5.0; Gaussian Inc.: Wallingford, 2008, p. 20.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Chattaraj, P.K.; Sarkar, U.; Roy, D.R. Electrophilicity Index. Chem. Rev., 2006, 106(6), 2065-2091. doi: 10.1021/cr040109f PMID: 16771443
- 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
- Miar, M.; Shiroudi, A.; Pourshamsian, K. Theoretical investigations on the HOMOLUMO 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
- 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
- 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
- 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
- Barret, R. Importance and evaluation of the polar surface area (PSA and TPSA). In: Therapeutical Chemistry; , 2018; p. 89-95.
- 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
- 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
- Martin, Y.C. A bioavailability score. J. Med. Chem., 2005, 48(9), 3164-3170. doi: 10.1021/jm0492002 PMID: 15857122
- 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
- Doherty, A.T.; Hayes, J.E.; Molloy, J.; Wood, C.; ODonovan, 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
Supplementary files
