Structural probing of HapR to identify potent phytochemicals to control Vibrio cholera through integrated computational approaches

• Main Authors: ul Qamar, Muhammad Tahir, Ahmad, Sajjad, Khan, Abbas, Mirza, Muhammad Usman, Ahmad, Sarfraz, Abro, Asma, Chen, Ling-Ling, Almatroudi, Ahmad, Wei, Dong-Qing
• Format: Article
• Published: Elsevier 2021
• Subjects: GE Environmental Sciences; QA75 Electronic computers. Computer science; QD Chemistry; QK Botany
• Online Access: http://eprints.um.edu.my/34289/

Cholera is a severe small intestine bacterial disease caused by consumption of water and food contaminated with Vibrio cholera. The disease causes watery diarrhea leading to severe dehydration and even death if left untreated. In the past few decades, V. cholerae has emerged as multidrug-resistant enteric pathogen due to its rapid ability to adapt in detrimental environmental conditions. This research study aimed to design inhibitors of a master virulence gene expression regulator, HapR. HapR is critical in regulating the expression of several set of V. cholera virulence genes, quorum-sensing circuits and biofilm formation. A blind docking strategy was employed to infer the natural binding tendency of diverse phytochemicals extracted from medicinal plants by exposing the whole HapR structure to the screening library. Scoring function criteria was applied to prioritize molecules with strong binding affinity (binding energy < -11 kcal/mol) and as such two compounds: Strychnogucine A and Galluflavanone were filtered. Both the compounds were found favourably binding to the conserved dimerization interface of HapR. One rare binding conformation of Strychnogucine A was noticed docked at the elongated cavity formed by alpha 1, alpha 4 and alpha 6 (binding energy of -12.5 kcal/mol). The binding stability of both top leads at dimer interface and elongated cavity was further estimated using long run of molecular dynamics simulations, followed by MMGB/PBSA binding free energy calculations to define the dominance of different binding energies. In a nutshell, this study presents computational evidence on antibacterial potential of phytochemicals capable of directly targeting bacterial virulence and highlight their great capacity to be utilized in the future experimental studies to stop the evolution of antibiotic resistance evolution.