Molecular dynamics simulation (MDS) analysis of Vibrio cholerae ToxT virulence factor complexed with docked potential inhibitors

Abstract

The ToxT transcription factor mediates the transcription of the two major virulence factors in Vibrio cholerae. It has a DNA binding domain made of α4, α5, α6, α7, α8, α9 and α10 helices that is responsible for the transcription of virulence genes. Therefore, it is of interest to screen ToxT against the ZINC ligand database containing data for a million compounds. The QSAR model identified 40 top hits for ToxT. Two target protein complexes with ligands Lig N1 and Lig N2 with high score were selected for molecular dynamics simulation. Simulation data shows that ligands are stable in the DNA binding domain of ToxT. Moreover, Lig N1 and Lig N2 passed pharmacological as well as ADME filters along with g-mmpbsa analysis with binding affinity of -199.831 kJ/mol for Lig N1 and - 286.951 kJ/mol for Lig N2. Moreover, no Lipinski and PhysChem violations were identified. It is further observed that these compounds were not inhibitors of P-glycoprotein, CYP450 and renal organic cation transporters. The LD50 of 2.5804 mol/kg for Lig N1 and 2.7788 mol/kg for Lig N2 was noted with acceptable toxicity index.

Structural insights into conformational stability of ESR1 and structure base screening of new potent inhibitor for the treatment of Breast Cancer

“…Explicit water molecules were de ned employing SPC (Simple Point Charge) model and a cubic period box with 1.0 nm distance (minimum) were set between protein and edge of the box. Following these, the protonation states of amino acid residues were set as per pH 7.0and the system was neutralized by adding counter ions [121][122][123][124][125][126][127][128][129][130][131].…”

Virtual Screening for Potential Phytobioactives as Therapeutic Leads to Inhibit NQO1 for Selective Anticancer Therapy

“…To neutralize the system, Na + ion (51.216 mM, with the charge of +31) and Cl − (56.173 mM, with a charge of −34) for NQO1 was used. This step automatically neutralizes the charge of the system during the study of the protein dynamics when the ligand is competing at the binding site [30,31]. Furthermore, a molecular dynamics simulation was carried out under some periodic boundary conditions in the atom numbers, pressure, and temperature (NPT) ensemble, with the temperature set to 300 K and 1 atmospheric pressure, then relaxed using the Desmond program's default relaxation methodology.…”