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 PknA and B. Comparatively, 57 was more surface-bound with highly unstable motions. Furthermore, 33 demonstrated similar binding patterns in PknA and B, involving conserved residues of their binding pockets. Both π and hydrogen interactions played crucial roles in the binding of 33, which altogether culminated in high ΔGs for both proteins. On the contrary, the binding of 57 was characterized by unfavorable interactions with possible repulsive effects on its optimal dual binding to both proteins, as evidenced by the relatively lowered ΔGs. These findings would significantly contribute to the rational structure-based design of novel and highly selective dual inhibitors of Mtb PknA and B.

In silico design of novel quinazoline-based compounds as potential Mycobacterium tuberculosis PknB inhibitors through 2D and 3D-QSAR, molecular dynamics simulations combined with pharmacokinetic predictions

“…Furthermore, the hydrogen bond interaction of compound 16 with Val95 (Figure 8c) shows a percentage occupancy (78.20 % H-bond occupation) than that of compound 12 (30.70 % H-bond occupation, Table 5), consistent with its greater in vitro activity against PknB. Olotu et al [46] have previously described that conventional hydrogen bonds of the pyrazole and quinazoline rings were made with PknB residues Phe19, Glu93, and Val95, and could play an important role in the stability of the inhibitor-enzyme complex. These data suggest that strong interactions involving the quinazoline, pyrazole and cyclopropyl core structures are important for high affinity binding to PknB.…”