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.
Highlights
The increase in the emergence of multi-drug and extensively drug resistant (MDR/XDR)Mycobacterium tuberculosis (Mtb) strains represents a major setback to the treatment of tuberculosis, which is thereby still as a major global threat [1]
Structural and sequential disparities among bacterial kinases of the serine/threonine protein kinases (STPKs) family have been widely described, which underlies our focus on the conformational dynamics of Protein kinases A (PknA) and PknB, the catalytic domains, relative to the binding of 33 and 57
Structural and sequential disparities among bacterial kinases of the STPK family have been widely described, which underlies our focus on the conformational dynamics of PknA and PknB, Thisparticularly presents an to understand howbinding the selective inhibitory activities of the compounds theapproach catalytic domains, relative to the binding of 33 and 57
Summary
The increase in the emergence of multi-drug and extensively drug resistant (MDR/XDR)Mycobacterium tuberculosis (Mtb) strains represents a major setback to the treatment of tuberculosis, which is thereby still as a major global threat [1]. The increase in the emergence of multi-drug and extensively drug resistant (MDR/XDR). Since the efficacies of existing anti-tubercular drugs have been thwarted by increasing incidences of drug resistance, there is the need for novel drugs that could disrupt crucial pro-resistance Mtb machinery. Mtb serine/threonine protein kinases (STPKs) have been pinpointed for their concerted involvement in mycobacterial viability [3,4]. This family of mycobacterial protein (11-membered) mediates protein phosphorylation events which play key roles in signal transduction to downstream pathways; typical of the two-component signaling cascade [5,6]. Post-translational modifications such as Molecules 2020, 25, 4247; doi:10.3390/molecules25184247 www.mdpi.com/journal/molecules
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