MOLECULAR DOCKING DYNAMICS OF SELECTED BENZYLIDENE AMINO PHENYL ACETAMIDES AS TMK INHIBITORS USING HIGH THROUGHPUT VIRTUAL SCREENING (HTVS)

KOPPULA JAYANTHI; SYED SUHAIB AHMED; MOHD ABDUL BAQI; MOHAMMED AFZAL AZAM

doi:10.22159/ijap.2024v16i3.50023

Authors

KOPPULA JAYANTHI Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0009-0003-9358-4278
SYED SUHAIB AHMED Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0000-0002-0290-2003
MOHD ABDUL BAQI Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0009-0000-3711-3568
MOHAMMED AFZAL AZAM Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0000-0001-9770-9371

DOI:

https://doi.org/10.22159/ijap.2024v16i3.50023

Keywords:

Thymidylate kinase (TMK), Molecular docking, Molecular dynamics simulations, MM-GBSA, ADME, HTVS

Abstract

Objective: Thymidylate kinase (TMK) plays a crucial role in bacterial DNA synthesis by catalyzing the phosphorylation of deoxythymidine monophosphate (dTMP) to form deoxythymidine diphosphate (dTDP). Consequently, this enzyme emerges as a promising target for developing novel antibacterial drugs. However, no antibiotics were reported for this target, especially active against Staphylococcus aureus thymidylate kinase.

Methods: Benzylidene acetamide-based ligands were examined for their potency using the in silico method. These novel ligand structures were built using ChemDraw software. The protein was retrieved from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) website. The molecular docking and binding free energy calculation by prime Molecular Mechanics in Generalized Bond Surface Area (MM-GBSA) was performed for selected ligands. A 100 ns molecular dynamic simulation was also performed to assess the stability of the potential ligand as TMK inhibitors.

Results: All ten molecules have shown good glide scores and hydrophobic and hydrogen hydrophobic hydrogen bonding interactions with Arg48, Arg36, and π-π stacking Phe66 in the TMK enzyme (PDB: 4HLC). Among them, N-(2-ethylphenyl)-2-(4-((4-nitrobenzylidene) amino) phenoxy) acetamide molecule had high XP-docking scores of-3.27 kcal/mol based on extra-precision data. Prime Molecular Mechanics in Generalized Bond Surface Area study (MM-GBSA) studies also showed promising binding affinities that are Δ_Bind (-65.80), Δ_Lipo (-28.55), and Δ_VdW (-55.10). Phe66 amino acid residue maintained continuous connections with the ligand during MD simulation. This ligand showed promising binding affinity with the SaTMK target.

Conclusion: The N-(2-ethylphenyl)-2-(4-((4-nitrobenzylidene) amino) phenoxy) acetamide ligand at the position of the benzene ring displayed nitrogen and oxygen group, thus indicating good potential activity as the inhibitor of TMK to treat antibacterial agents.

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