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

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 ΔGBind of −52.98 kcal/mol, ΔGLipo of −27.75 kcal/mol, and ΔGVdW 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.