Ligand-based pharmacophore modelling, in silico virtual screening, molecular docking and molecular dynamic simulation st
- PDF / 2,510,045 Bytes
- 14 Pages / 595.276 x 790.866 pts Page_size
- 90 Downloads / 206 Views
ORIGINAL PAPER
Ligand‑based pharmacophore modelling, in silico virtual screening, molecular docking and molecular dynamic simulation study to identify novel Francisella tularensis ParE inhibitors Vidyasrilekha Yele1 · Mohammad Afzal Azam1 · Srikanth Jupudi1 Received: 8 February 2020 / Accepted: 29 June 2020 © Institute of Chemistry, Slovak Academy of Sciences 2020
Abstract ParE, a subunit of topoisomerase IV, is involved in the management of DNA topology and validated to be an attractive target for the development of antibacterial agents. Availability of the crystal structure of Francisella tularensis in combination with one of the pyrrolo [2,3-d] pyrimidine-2-thiolinhibitor facilitated us to emphasize the combined computational approach for discovering the presumed binding mode of selected inhibitors into the binding pocket of ParE (pdb. 4HY1). In the current study, pharmacophore modelling and 3D-QSAR studies were performed using 33 reported F. tularensis ParE inhibitors having pKi ranging from 5.06 to 9.00. The developed five featured pharmacophore model, DHHRR_1 was statistically validated with different parameters like Q2 (0.66), R2 (0.99) and F value (682) at four-component partial least squares factor. Enrichment analysis was performed to validate the generated pharmacophore model. Extra-precision molecular docking, binding free energy calculation using PRIME MM-GBSA were performed for the selected inhibitors. Induced fit docking was performed for the highest active inhibitor 16. The highest-ranked induced fit docked complex 16/4HY1 was used to run a 50 ns molecular dynamic simulation to validate the stability. Further, in silico High Throughput Virtual Screening was performed using 22 lakhs chemical database molecules to identify the potential virtual hits and predicted activity was found for the virtual hits. These results provide promising strategies for the development of novel molecules with better inhibitory activity against F. tularensis ParE.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11696-020-01274-3) contains supplementary material, which is available to authorized users. * Mohammad Afzal Azam [email protected]; [email protected] 1
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamilnadu, India
13
Vol.:(0123456789)
Chemical Papers
Graphic abstract
Keywords Pharmacophore modelling · Molecular docking · Molecular dynamics simulation · ParE inhibitors
Introduction Antibacterial resistance is considered a global threat to mankind with a high rate of mortality and morbidity which needs dire attention (Levy and Marshall 2004). In addition, there is an increased demand for the novel types of antibacterials acting on different unexploited targets to overcome the prevailing resistance issue (Worthington and Melander 2013). The adenosine triphosphate (ATP)dependent bacterial DNA gyrase (GyrA and GyrB) and topoisomerase IV (ParC and ParE) enzymes are hetero
Data Loading...
