In Silico Discovery of Novel Ligands for Anti-Tubercular Targets using Computer Aided Drug Design

Abstract

Tuberculosis still remain one of the most burdened infectious disease in the world especially with the emergence of drug resistance to the current drug regimen. It is the second most leading reason for infectious disease related death and with the emergence of MDR and XDR TB there is a consistent need to develop novel drugs with disparate modes of actions. Our objective is to design novel benzimidazole derivatives with anti-tubercular activity. A series 4-(1H-benzimidazole-2-ylmethyl) aniline derivatives were designed using ACD/Chem Sketch and their molecular properties and ADMET properties were designed using BIOVIA Discovery Studio. Target proteins were chosen in comparison to the standard drug isoniazid which are (Enoyl-(acyl-carrier-protein) reductase, Catalase-peroxidase, Dihydrofolate reductase) and a newly developed target protein MmpL3 were taken. CDOCKER energy and CDOCKER INTERACTION energy of both ligand and standard drug on all the target candidates were determined using BIOVIA Discovery Studio. The CDOCKER energy and CDOCKER INTERACTION energy of the newly developed ligand on the above mentioned targets were found to be higher in compared to standard drug, which signifies that the ligand molecules have higher specificity towards the target than the standard drug. Newly designed derivatives were found to have a better docking score towards the target protein enoyl-acyl carrier protein reductase and MmpL3 both of which aids to the development of mycobacterial cell wall synthesis therefore blocking both or either one of the protein will result in the depletion of mycolic acid concentration in mycobacterial cell wall resulting in loss of structural integrity of bacterial cell wall resulting in mycobacterial death.