Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of New Drugs against Human Topoisomerase I Receptor

Abstract

Human Topoisomerase I (hTop1p) is a ubiquitous enzyme that relaxes supercoiled DNA through a conserved mechanism involving transient breakage, rotation, and binding. Htop1p is the molecular target of the chemotherapeutic drug camptothecin (CPT). It causes the hTop1p-DNA complex to slow down the binding process and clash with the replicative machinery during the S phase of the cell cycle, forcing cells to activate the apoptotic response. This gives hTop1p a central role in cancer therapy. Recently, two artesunic acid derivatives (compounds c6 and c7) have been proposed as promising inhibitors of hTop1p with possible antitumor activity. We used several computational approaches to obtain in silico confirmations of the experimental data and to form a comprehensive dynamic description of the ligand-receptor system. We performed molecular docking analyses to verify the ability of the two new derivatives to access the enzyme-DNA interface, and a classical molecular dynamics simulation was performed to assess the capacity of the two compounds to maintain a stable binding pose over time. Finally, we calculated the noncovalent interactions between the two new derivatives and the hTop1p receptor in order to propose a possible inhibitory mechanism like that adopted by CPT.

Synthesis, Characterization and Response of Newer Benzamidine Analogues against Porphyromonas gingivalis mediated Peri-Implantitis

“…The molecular docking study was performed to establish the binding ability of the NBA to the binding site of gingipain K (Kgp) of P. gingivalis (PDB ID: 4RBM) [27]. The docking scores of designed molecules are presented in Table-1.…”

Synthesis, Characterization, Docking Studies and in vitro Response of New Camptothecin Derivatives towards Oral Squamous Cell Carcinoma

“…The molecular docking study was performed to establish the binding ability of the camptothecin derivatives to the binding site of Human DNA Topoisomerase-1 (Top-1, 70 Kda) complexed with A 22 Base Pair DNA Duplex (PDB ID: 1T8I) [27]. The docking scores of designed molecules are presented in Table-1.…”

Improving the thermostability of Pseudoalteromonas Porphyrae κ-carrageenase by rational design and MD simulation

“…RMSF is a measure of the displacement of amino acid residues around their average position within a defined time period, and it can detect the highly flexible regions in proteins (Biswas et al 2020 ). The low RMSF value indicates that the residue has low flexibility during the simulation process, having strong stiffness and stability (Madeddu et al 2022 ). In this study, the improved rigidity of F5 finger and R150 residue, the increased flexibility of some loops and R259 residue in S190R could account for the improvement of thermostability of the mutant κ-carrageenase.…”