A MOLECULAR MODELLING APPROACH FOR STRUCTURE-BASED VIRTUAL SCREENING AND IDENTIFICATION OF NOVEL ISOXAZOLES AS POTENTIAL ANTIMICROBIAL AGENTS AGAINST S. AUREUS

JUDY JAYS; J. SARAVANAN

doi:10.22159/ijpps.2024v16i4.49731

Authors

JUDY JAYS Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ramaiah University of Applied Sciences, Bengaluru-560054, India
J. SARAVANAN Faculty of Pharmaceutical Sciences, PES University, Bengaluru-560100, India

DOI:

https://doi.org/10.22159/ijpps.2024v16i4.49731

Keywords:

Antimicrobial, Isoxazoles, Molecular docking, S. aureus, In silico, ADME

Abstract

Objective: Universal use of antibacterial agents and swift development of resistance by the microorganisms pose a major threat to public health. Hence, there is a pressing need to develop novel antimicrobials. Isoxazole derivatives exhibiting versatile biological activities have been widely used as important scaffolds in the field of drug designing.

Methods: Twenty isoxazole derivatives were virtually screened by means of the molecular docking approach in order to identify potential antimicrobials against the most common disease-causing bacteria, S. aureus. In silico studies were done to detect the selectivity of the novel isoxazole derivatives for the selected bacterial protein targets using ‘Glide’. In silico docking was carried out on few essential enzymes of S. aureus; Dihydrofolate reductase (DHFR), DNA gyrase, Dihydropteroate Synthetase (DHPS), Pyuvate kinase (PK). The compounds were subjected to energy minimization, followed by optimization and minimization of protein and generation of 3D grid at its active site. The ligands were subjected to molecular docking the Standard Precision and Extra Precision modes.

Results: Docking of the compounds with Pyruvate Kinase and dihydrofolate reductase are quite encouraging.2C (4-hydroxy) and 2D (4-hydroxy) analogues gavea G Score of-8.33 and-8.64 with DHFR and Pyruvate Kinase respectively. However, the dock scores for the other target proteins indicate that the scaffolds have not bound with those bacterial targets. Moreover, ADME studies indicate that the derivatives do not show any violations in the rules for the requirements of orally active drugs.

Conclusion: Study suggests that the derivatives 2C (4-hydroxy) and 2D(2-hydroxy) specifically bind to the active site of PK and DHFR. In silico ADME studies predicted the compounds to be “drug-like.” Hence the hydroxy derivatives may be considered as leads for further structural modifications to arrive at potential anti-bacterial agents.

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References

Poolman JT, Anderson AS. Escherichia coli and Staphylococcus aureus: leading bacterial pathogens of healthcare-associated infections and bacteremia in older-age populations. Expert Rev Vaccines. 2018;17(7):607-18. doi: 10.1080/14760584.2018.1488590, PMID 29902092.

Alghizzi M, Shami A. The prevalence of Staphylococcus aureus and methicillin-resistant staphylococcus aureus in milk and dairy products in Riyadh, Saudi Arabia. Saudi J Biol Sci. 2021 Dec;28(12):7098-104. doi: 10.1016/j.sjbs.2021.08.004, PMID 34867012.

Barrero LI, Castillo JS, Leal AL, Sanchez R, Cortes JA, Alvarez CA. Economic burden of methicillin-resistant Staphylococcus aureus bacteremia in critical care patients in hospitals in Bogota. Biomedica. 2014;34(3):345-53. doi: 10.1590/S0120-41572014000300005, PMID 25504122.

Rubin RJ, Harrington CA, Poon A, Dietrich K, Greene JA, Moiduddin A. The economic impact of staphylococcus aureus infection in New York City Hospitals. Emerg Infect Dis. 1999;5(1):9-17. doi: 10.3201/eid0501.990102, PMID 10081667.

Deresinski S. Methicillin-resistant staphylococcus aureus: an evolutionary, epidemiologic, and therapeutic odyssey. Clin Infect Dis. 2005;40(4):562-73. doi: 10.1086/427701, PMID 15712079.

Ippolito G, Leone S, Lauria FN, Nicastri E, Wenzel RP. Methicillin-resistant Staphylococcus aureus: the superbug. Int J Infect Dis. 2010;14 Suppl 4:S7-S11. doi: 10.1016/j.ijid.2010.05.003, PMID 20851011.

Zhu J, Mo J, Lin HZ, Chen Y, Sun HP. The recent progress of isoxazole in medicinal chemistry. Bioorg Med Chem. 2018;26(12):3065-75. doi: 10.1016/j.bmc.2018.05.013, PMID 29853341.

Judy J, Mohan S, Saravanan J. Molecular docking studies of novel furan-azetidine hybrids as potential inhibitors of Escherichia C coli. Indian J Pharm Educ Res. 2019;53(3):S328-31.

Judy J, Mohan S, Saravanan J. Molecular docking studies of novel aminopyrimidines as potent antifungal agents. Chem Methodol. 2019;3(4):442-50.

Kaur H, Singh J, Narasimhan B. Antimicrobial, antioxidant and cytotoxic evaluation of diazenyl chalcones along with insights to mechanism of interaction by molecular docking studies. BMC Chem. 2019;13(1):87. doi: 10.1186/s13065-019-0596-5, PMID 31384834.

Bennett BC, Xu H, Simmerman RF, Lee RE, Dealwis CG. Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase. J Med Chem. 2007;50(18):4374-81. doi: 10.1021/jm070319v, PMID 17696333.

Liu J, Bolstad DB, Bolstad ES, Wright DL, Anderson AC. Towards new antifolates targeting eukaryotic opportunistic infections. Eukaryot Cell. 2009;8(4):483-6. doi: 10.1128/EC.00298-08, PMID 19168759.

Li X, Hilgers M, Cunningham M, Chen Z, Trzoss M, Zhang J. Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines. Bioorg Med Chem Lett. 2011;21(18):5171-6. doi: 10.1016/j.bmcl.2011.07.059, PMID 21831637.

Hawser S, Lociuro S, Islam K. Dihydrofolate reductase inhibitors as antibacterial agents. Biochem Pharmacol. 2006;71(7):941-8. doi: 10.1016/j.bcp.2005.10.052, PMID 16359642.

Chougala BM, Samundeeswari S, Holiyachi M, Shastri LA, Dodamani S, Jalalpure S. Synthesis, characterization and molecular docking studies of substituted 4-coumarinylpyrano[2,3-c]pyrazole derivatives as potent antibacterial and anti-inflammatory agents. Eur J Med Chem. 2017;125(1):101-16. doi: 10.1016/j.ejmech.2016.09.021, PMID 27657808.

Zoraghi R, Worrall L, See RH, Strangman W, Popplewell WL, Gong H. Methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase as a target for bis-indole alkaloids with antibacterial activities. J Biol Chem. 2011;286(52):44716-25. doi: 10.1074/jbc.M111.289033, PMID 22030393.

Zoraghi R, See RH, Axerio Cilies P, Kumar NS, Gong H, Moreau A. Identification of pyruvate kinase in methicillin-resistant staphylococcus aureus as a novel antimicrobial drug target. Antimicrob Agents Chemother. 2011;55(5):2042-53. doi: 10.1128/AAC.01250-10, PMID 21357306.

Reece RJ, Maxwell A. DNA gyrase: structure and function. Crit Rev Biochem Mol Biol. 1991;26(3-4):335-75. doi: 10.3109/10409239109114072, PMID 1657531.

Tse Dinh YC. Targeting bacterial topoisomerases: how to counter mechanisms of resistance. Future Med Chem. 2016;8(10):1085-100. doi: 10.4155/fmc-2016-0042, PMID 27285067.

Charrier C, Salisbury AM, Savage VJ, Duffy T, Moyo E, Chaffer Malam N. Novel bacterial topoisomerase inhibitors with potent broad-spectrum activity against drug-resistant bacteria. Antimicrob Agents Chemother. 2017;61(5):513-9. doi: 10.1128/AAC.02100-16, PMID 28223393.

Singh SB, Kaelin DE, Wu J, Miesel L, Tan CM, Black T. Tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of left-hand-side moiety (Part-2). Bioorg Med Chem Lett. 2015;25(9):1831-5. doi: 10.1016/j.bmcl.2015.03.044, PMID 25851938.

Schrodinger. LiG Prep software. version 2.5. New York: LLC; 2011.

Schrodinger. Maestro. version 11. New York: LLC; 2011.

Glide. version 6.7, User M, Schrödinger LLC. New York; 2015.

Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004;47(7):1739-49. doi: 10.1021/jm0306430, PMID 15027865.

Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem. 2004;47(7):1750-9. doi: 10.1021/jm030644s, PMID 15027866.

Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006;49(21):6177-96. doi: 10.1021/jm051256o, PMID 17034125.

Daina A, Michielin O, Zoete V. Swiss ADME: 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, PMID 28256516.

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1-3):3-26. doi: 10.1016/s0169-409x(00)00129-0, PMID 11259830.

Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem. 1999;1(1):55-68. doi: 10.1021/cc9800071, PMID 10746014.

Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45(12):2615-23. doi: 10.1021/jm020017n, PMID 12036371.

Muegge I, Heald SL, Brittelli D. Simple selection criteria for drug-like chemical matter. J Med Chem. 2001;44(12):1841-6. doi: 10.1021/jm015507e, PMID 11384230.

Pathania S, Singh PK. Analyzing FDA-approved drugs for compliance of pharmacokinetic principles: should there be a critical screening parameter in drug designing protocols? Expert Opin Drug Metab Toxicol. 2021;17(4):351-4. doi: 10.1080/17425255.2021.1865309, PMID 33320017.

Jays J, Mohan S, Saravanan J. Molecular docking studies of some novel furan derivatives as potent inhibitors of staphylococcus Aureus. Indian J Pharm Res. 2019;11(1):200-6.

Jays J, Mohan S, Saravanan J. Molecular docking studies of novel furan-azetidine hybrids as potential inhibitors of Escherichia C coli. Indian J Pharm Educ Res. 2019;53(3s):s325-31. doi: 10.5530/ijper.53.3s.102.

Madriwala B, Jays J, Sai CS. Molecualar docking and computational pharmacokinetic study of some novel coumarin-benzothiazoleschiff’s bases for antimicrobial activity. Int J Pharm Pharm Sci. 2022;14(8):16-21.