Computational modeling for the design and optimization of novel small molecules as potential inhibitors of the mycobacterial cytochrome bc1 complex

Abstract

Introduction: Tuberculosis (TB) is a leading infectious disease worldwide and is regarded as the second leading cause of mortality, trailing only the human immunodeficiency virus. TB chemotherapy is challenged by the continued rise of drug resistance. The terminal oxidases of the oxidative phosphorylation pathway play a significant role in the survival and growth of M. tuberculosis, targeting these components lead to inhibition of M. tuberculosis. This epidemic urges the need to discover anti-TB drugs with novel modes of action. Many drug candidates targeting various components of the electron transport chain in M. tuberculosis have recently been discovered. The QcrB subunit of the cytochrome bc1 complex is one of the most important components of the electron transport chain in M. tuberculosis, and it has emerged as the novel target for several promising candidates. The development of small-molecule inhibitors against cytochrome bc1 complex has been a challenging task. Despite extensive research, the 3D structure of cytochrome bc1 complex for the M. tuberculosis was not available in the Protein data bank, making it difficult to understand how the QcrB subunit interacts with its inhibitors and to create new anti-tuberculosis scaffolds. The main goal of the study was to design the small molecules against the mycobacterial cytochrome bc1 complex one of the vital targets of the electron transport chain in the mycobacterium using a structure-based drug-design approach (SBDD). Sequence alignments also showed a significant degree of similarity between the QcrB subunit of the cytochrome bc1 complex from M. tuberculosis and M. smegmatis. Thus, QcrB inhibitors would have a similar binding mechanism and effect on the activity of the cytochrome bc1 complex in M. smegmatis. As a result, the cryo-EM structure of the mycobacterial cytochrome bc1 complex of M. smegmatis (PDB ID: 6ADQ) was chosen as a target protein in this study. newline