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

Adeniyi T Adewumi; Wande M Oluyemi; Nonhlanhla Adewumi; Yemi A Adekunle; Mohamed Issa Alahmdi; Nader E Abo-Dya; Mahmoud E S Soliman

doi:10.2174/1568026623666230125124433

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

Curr Top Med Chem. 2023;23(12):1065-1080. doi: 10.2174/1568026623666230125124433.

Authors

Adeniyi T Adewumi^{1

2}, Wande M Oluyemi^{2

3}, Nonhlanhla Adewumi^{2

4

5}, Yemi A Adekunle^{2

6

7}, Mohamed Issa Alahmdi⁸, Nader E Abo-Dya^{9

10}, Mahmoud E S Soliman¹

Affiliations

¹ Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
² Research Laboratories for Rational Design of Drugs and Biomaterials, Isiphephelo Court, Tsakane, 1550, Brakpan, Johannesburg East Rand, Gauteng, South Africa.
³ Department of Pharmaceutical and Medicinal Chemistry, College of Pharmacy, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria.
⁴ Department of Chemistry, Faculty of Applied and Computer Sciences, Vaal University, Vanderbijl Park, South Africa.
⁵ Chemical research Laboratory, BetaChem Pty Ltd, ERF5 Producta Road, Driemanskap, Heidelberg, 1441, Gauteng, South Africa.
⁶ Laboratory for Natural Products and Biodiscovery Research, Pharmaceutical Chemistry Department, Faculty of Pharmacy, University of Ibadan, Nigeria.
⁷ Centre for Natural Products Discovery (CNPD), School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom.
⁸ Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, 7149, Saudi Arabia.
⁹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tabuk University, Tabuk, 71491, Saudi Arabia.
¹⁰ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.

PMID: 36698229
DOI: 10.2174/1568026623666230125124433

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 and_tr2DG167 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: Flap-dimer dynamics; Hydrophobic interaction; Indazole sulphonamide; Molecular mechanism; Mtb β-ketoacyl-ACP synthase; Structure-based design.; TriC-α angle metrics; Virulence/drug resistance.

MeSH terms

Catalytic Domain
Computer Simulation
Molecular Dynamics Simulation
Mycobacterium tuberculosis*
Protein Binding