Virtual Screening, Docking, ADMET and Molecular Dynamics: A Study to Find Novel Inhibitors of Mycobacterium tuberculosis Targeting QcrB

Abstract: A major difficulty in the treatment of mycobacterial infection is its resistance against anti-mycobacterial drugs. Exploration of diverse targets, the search for novel chemical scaffolds and different methods of tuberculosis treatment are all basic measures needed in this perspective. In the same context, mycobacterial oxidative phosphorylation has received a lot of interest. It includes the electron transport system, which encompasses the cytochrome B component of the cytochrome bc1 complex (QcrB) which is a promising therapeutic target. The anti-tubercular drug Q203 (Telacebec), which is currently in phase 2 clinical trial, inhibits cytochrome B. The present study includes virtual screening studies from the ‘Zinc15’ chemical database, taking Q203 as a reference molecule, the creation of protein using homology modeling, molecular docking as well as simulation studies. The constructed protein showed considerable reliability, as results of the Ramachandran plot showed 92.8% amino acid residues in the favoured region, ERRAT score (overall quality factor) of 92.48% with ProSA (Z score) of –5.78. The hit molecules identified by structure-based virtual screening follow the Lipinski rule of five. The docking results indicated binding affinity values ranging from –7.19 to –9.10 kcal/mol. The top three compounds were ZINC64033452, ZINC3816287 and ZINC3830215, each having a higher docking score than the reference ligand (–7.70 kcal/mol). Leu174, Pro306, Ser304, Leu180, Glu314 and Thr313 are among the residues that cover the protein’s active site. The H-bond was observed in docking studies for Q203 and top three molecules from amino acid residues Glu314 and Thr313 and was consistent throughout dynamics studies. In a dynamics run of 20 ns, a stable RMSD was found after 8 ns for hit-molecules and Q203. Based on potential findings, we report that selected candidates are more likely to be used as anti-mycobacterial agents or as starting leads for the development of novel and potent anti-tubercular agents.