Probing the Highly Disparate Dual Inhibitory Mechanisms of Novel Quinazoline Derivatives against Mycobacterium tuberculosis Protein Kinases A and B.

ABSTRACT: Mycobacterium tuberculosis (Mtb) serine/threonine (Ser/Thr) Protein kinases A (PknA) and B (PknB) have been identified as highly attractive targets for overcoming drug resistant tuberculosis. A recent lead series optimization study yielded compound 33 which exhibited potencies ~1000 times higher than compound 57. This huge discrepancy left us curious to investigate the mechanistic 'dual' (in)activities of the compound using computational methods, as carried out in this study. Findings revealed that 33 stabilized the PknA and B conformations and reduced their structural activities relative to 57. Optimal stability of 33 in the hydrophobic pockets further induced systemic alterations at the P-loops, catalytic loops, helix Cs and DFG motifs of

SUBMITTER: Olotu FA 

PROVIDER: S-EPMC7571077 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature