Identification of potential inhibitors against Corynebacterium diphtheriae MtrA response regulator protein; an in-silico drug discovery approach.

Autor: Khalid Z; School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China. Electronic address: zunera.khalid@bs.qau.edu.pk., Shamim A; Department of Computer Science, University of Agriculture Faisalabad, Pakistan; Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom., Saadh MJ; Faculty of Pharmacy, Middle East University, Amman, Jordan., Alafnan A; Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail, Saudi Arabia., Alaraj M; Faculty of Pharmacy, Jerash Private University, Jerash, Jordan., Butt MH; Department of Computer Science, University of Agriculture Faisalabad, Pakistan., Ashraf T; National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
Jazyk: angličtina
Zdroj: Journal of molecular graphics & modelling [J Mol Graph Model] 2024 Dec; Vol. 133, pp. 108858. Date of Electronic Publication: 2024 Sep 01.
DOI: 10.1016/j.jmgm.2024.108858
Abstrakt: Corynebacterium diphtheriae is a multi-drug resistant bacteria responsible for the life-threatening respiratory illness, diphtheria which can lead to severe Nervous system disorders, mainly infecting the lungs, heart, and kidneys if left untreated. In the current study, Corynebacterium diphtheriae MtrA response regulator protein was targeted, which regulates a two-component system of bacterial pathogenesis, and initiates DNA replication and cell division. In the current study a computational approach have been described for drug development against C. diphtheriae infections by inhibiting MtrA protein by small molecules acting as potential inhibitors against it. Molecular docking analysis of the equilibrated MtrA protein revealed compound-0.2970, compound-0.3029, and compound-0.3016 from Asinex Library as the promising inhibitors based on their lowest binding energies (-9.8 kJ/mol, -9.2 kJ/mol, and -8.9 kJ/mol), highest gold scores (40.53, 47.41, and 48.41), drug-likeness and pharmacokinetic properties. The MD simulation studies of the identified top-ranked inhibitors at 100 ns elucidated the system stability and fluctuations in the binding pocket of MtrA protein. Molecular Dynamics Simulations of the top three docked complexes further revealed that the standard binding pocket was retained ensuring the system stability. The rearrangements of H-bonds, van der Waals, pi-pi, and solid hydrophobic interactions were also observed. The binding free energy calculations (MM/PBSA and MM/GBSA) suggested a fundamental binding capability of the ligand to the target receptor MtrA. Therefore, the current study has provided excellent candidates acting as potent inhibitors for developing therapeutic drugs against C. diphtheriae infections. However, in vivo and in vitro animal experiments and accurate clinical trials are needed to validate the potential inhibitory effect of these compounds.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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