IDENTIFICATION OF BENZYLIDENE AMINO PHENOL INHIBITORS TARGETING THYMIDYLATE KINASE FOR COLON CANCER TREATMENT THROUGH IN SILICO STUDIES

MOHD ABDUL BAQI; KOPPULA JAYANTHI; RAJESH KUMAR R.

doi:10.22159/ijap.2024v16i4.50874

Authors

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
KOPPULA JAYANTHI Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India
RAJESH KUMAR R. Department of Pharmaceutical Biotechnology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India

DOI:

https://doi.org/10.22159/ijap.2024v16i4.50874

Keywords:

Thymidylate kinase (TMK), Molecular docking, Molecular dynamics (MD) simulations, MM-GBSA, High-throughput virtual screening (HTVS), ADME profiles, Cancer therapy, Colorectal cancer (CRC), Human thymidylate kinase (HaTMK)

Abstract

Objective: Thymidylate kinase (TMK) is pivotal in bacterial DNA synthesis, facilitating the conversion of Deoxythymidine Monophosphate (dTMP) into Deoxythymidine Diphosphate (dTDP). This crucial role positions TMK as an attractive target for the creation of innovative anti-cancer therapies. To date, there have been no anti-cancer medications developed specifically targeting this enzyme.

Methods: The investigation involved screening benzylidene derivatives as potential ligands for their efficacy. This process was executed through the utilization of the Glide module for molecular docking, followed by an Absorption, Distribution, Metabolism, and Excretion (ADME) analysis via Qikprop. Subsequently, the Prime Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) approach was employed to evaluate the binding free energy of these ligands. To further assess the stability of these ligands as inhibitors of Human Thymidylate Kinase (HaTMK), molecular dynamics (MD) simulations were conducted over a 100 nanosecond timeframe.

Results: Among the screened molecules, ten exhibited significant binding affinity, engaging in hydrogen and hydrophobic interactions with the Asp15, Phe105, and Phe72 residues of the HaTMK enzyme (PDB ID: 1E2D). Notably, the molecule 4-((4-dichlorobenzylidene) amino) phenol demonstrated the highest docking score with an Extra Precision (XP)-docking value of −6.33 kcal/mol, indicating a strong binding affinity based on extra-precision docking. Further analysis through Prime MM-GBSA revealed notable binding energies, including a ΔG_Bind of −52.98 kcal/mol, ΔG_Lipo of −27.75 kcal/mol, and ΔG_VdW of −47.70kcal/mol, suggesting significant interaction strength. Throughout the MD simulations, interactions between the ligand and the Glu152 and Phe105 residues remained stable, underlining the molecule's potential as a TMK inhibitor.

Conclusion: The ligand 4-((4-dichlorobenzylidene) amino)phenol, characterized by its benzene ring, benzylidene moiety, and oxygen group, engages effectively with the HaTMK protein's active sites. This interaction showcases its promising potential as an inhibitor of HaTMK, positioning it as a viable candidate for the treatment of colon cancer.

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