Validation of potential inhibitors for SrtA against Bacillus anthracis by combined approach of ligand-based and molecular dynamics simulation

Abstract

The development of SrtA inhibitors targeting the biothreat organism namely Bacillus anthracis was achieved by the combined approach of pharmacophore modeling, binding interactions, electron transferring capacity, ADME, and Molecular dynamics studies. In this study, experimentally reported Ba-SrtA inhibitors (pyridazinone and pyrazolethione derivatives) were considered for the development of enhanced pharmacophoric model. The obtained AAAHR hypothesis was a pure theoretical concept that accounts for common molecular interaction network present in experimentally active pyridazinone and pyrazolethione derivatives. Pharmacophore-based screening of AAAHR hypothesis provides several new compounds, and those compounds were treated with four phases of docking protocols with combined Glide-QPLD docking approach. In this approach, scoring and charge accuracy variations were seen to be dominated by QM/MM approach through the allocation of partial charges. Finally, we reported the best compounds from binding db, Chembridge db, and Toslab based on scoring values, energy parameters, electron transfer reaction, ADME, and cell adhesion inhibition activity. The dynamic state of interaction and binding energy assess that new compounds are more active inside the binding pocket and these compounds on experimental validations will survive as better inhibitors for targeting the cell adhesion mechanism of Ba-SrtA.

Keywords:

• B. anthracis
• cell adhesion
• molecular dynamics
• QPLD
• partial charges
• SrtA
• sortase

Acknowledgment

The authors thankfully acknowledge the CSIR for research funding and fellowship grants (Ref. No: 37(1491)/11/EMR-II) and Alagappa University. One of the authors, Chandrabose Selvaraj, gratefully acknowledges CSIR for the Senior Research Fellowship (SRF). The authors thank Mr. Sankar Venkatesh, Alagappa University and suggestions from the anonymous reviewers were cordially appreciated.