Structure elucidation and identification of novel lead molecules against Sulfur import protein cysA of Mycobacterium tuberculosis.

Abstract

The present work considers the Sulphate import ABC transporter protein (cysA) as a potential drug target for the identification of inhibitors for the protein. The ABC (ATP binding cassette) transporters play a crucial role in the survival and virulence of Mycobacterium tuberculosis by the acquisition of micronutrients from host tissue. The 3D structural features of the cysA protein are built. Molecular scaffolds are identified by implementing active site identification, ADME properties, Virtual Screening, and a few other computational techniques. The theoretical model of cysA is predicted using homology modeling protocols, and the structure is validated by various validation methods. The prediction of partial dimer formation through protein-protein docking methods gave insight into the conformational changes taking place in the cysA protein. The natural substrate ATP is docked with cysA protein that confirms the ATP binding site. To find the drug-like compounds, virtual screening studies were carried out around the active site by several ligand databases. The findings demonstrate the significance of residues SER41, GLY42, ARG50, GLN85, HIS86, LYS91, ARG142, and ASP161 in drug-target interactions. The docking studies of existing TB drugs against cysA were also performed. The result analysis shows that none of the existing drugs inhibits the ATP active site, which confirms cysA as a promising drug target. Using in-silico methods, the ADME parameters of a few chosen ligand molecules are predicted and contrasted with the ADME characteristics of the available TB medications. The results revealed the values of ADME parameters of selected ligand molecules are more permissible than existing TB drugs, which emphasizes the drug-like activity of ligand molecules by inhibition of cysA proteins. The structural data, active site information, and selected ligand molecules help in the identification of new therapeutic scaffolds for Tuberculosis.