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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

Probing into the Flap-dimer Dynamics of the Mycobacterium tuberculosis Kasa Enzyme Binding Landscape Provides the Underlying Inhibitory Mechanisms of JSF-3285 and 5G

Author(s): Adeniyi T. Adewumi, Wande M. Oluyemi, Nonhlanhla Adewumi, Yemi A. Adekunle, Mohamed Issa Alahmdi, Nader E. Abo-Dya and Mahmoud E.S. Soliman*

Volume 23, Issue 12, 2023

Published on: 08 March, 2023

Page: [1065 - 1080] Pages: 16

DOI: 10.2174/1568026623666230125124433

Price: $65

Abstract

Background: β-ketoacyl-ACP synthase I (KasA I) enzyme is crucial in mycolic acid synthesis via catalytic condensation reactions, hence implicated in M. tuberculosis’s virulence and drug resistance. Presently, there is no known potent KasA inhibitor; thiolactomycin lacks potency. Recently reported indazole compounds JSF-3285/tr1DG167 and 5G/tr2DG167 inhibit the KasA through binding to the substrate cavity. However, the molecular mechanism is still unclear, and the unknown resistance mechanisms raise concerns about JSF-3285's novelty.

Methods: This study is the first to report the flap dimer opening and closing of the KasA pocket using combined metrics to define the symmetry impact of the flap-dimer motions and investigate the underlying inhibitory mechanism of tr1DG167 andtr2DG167 using all-atom MD simulation.

Results: The distance/d1 between the flap (PRO147) and dimer (LEU205) residues; TriC-α angle (θ1: PRO147-VAL83-LEU205 & θ2: PRO147-GLU199-LEU205); and the dihedral angle (Φ) were applied to investigate the flap “twisting” and dimer shift closing due to concerted motion by adjacent glycine-rich and glutamic acid-rich loops around the active site during the binding pocket’s opening. The full flap-dimer of the unbound opens at 230 ns (d1 = 21.51 Å), corresponding to the largest TriC-α angle θ1 44.5° as θ2 is unreliable to describe the flap-dimer motion. The overall averages θ1 and θ2 for the bounds were ~23.13° and ~23.31°, respectively. Thus, the degree of KasA flap dimer opening is best investigated by distance and θ1. BFE (Kcal/mol) of -44.05 (tr1DG167) showed a higher affinity for the pocket than tr2DG167-KasA (-32.16). Both tr1DG167 and tr2DG167 formed hydrophobic interactions with LEU116, GLY117, ALA119, and tr1DG167 formed strong H-bonds with GLU199. The average RMSD of 2.80 Å (Apo) and RoG of 20.97 Å showed that KasA is less stable and less tightly packed without the inhibitors.

Conclusion: These findings provide a background for a new structure-based design of novel KasA inhibitors.

Keywords: Mtb β-ketoacyl-ACP synthase, Indazole sulphonamide, Virulence/drug resistance, Flap-dimer dynamics, Molecular mechanism, TriC-α angle metrics, Hydrophobic interaction, Structure-based design.

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