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

Article

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

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 us-ing 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 adja-cent 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 av-erages 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.

2021-07-01·Scientific African

Ligand-protein interactions of plant-isolated (9z,12z)-octadeca-9,12-dienoic acid with Β-ketoacyl-Acp synthase (KasA) in potential anti-tubercular drug designing

Article

作者: Bvunzawabaya, Jonathan T ; Tolo, Casim U ; Sesaazi, Duncan C ; weisheit, Anke ; Ngwira, Kennedy J. ; Mtewa, Andrew G. ; Tolo, Casim U. ; Okella, Hedmon ; Weisheit, Anke ; Ogwang, Patrick E ; Ogwang, Patrick E. ; Mtewa, Andrew G ; Maghembe, Reuben ; Ngwira, Kennedy J ; Sesaazi, Duncan C. ; Bvunzawabaya, Jonathan T. ; Lampiao, Fanuel

Mycobacterium tuberculosis remains one of the world's contributors to mortality. With the emergence of SARS-CoV-2 coinfections, patients with TB are predisposed to being more heavily weighed down by COVID-19 disease and its opportunistic coinfections. The severity of the disease coupled with drug resistance on the currently used drugs warrants for the search for alternative remedies from synthetic agents, semisynthetics and natural products that include plants. Africa is rich in plant diversity with a promise as sources of drug agents, one of which is Eichhornia crassipes. This work aimed at isolating a fatty acid and dock it to β-ketoacyl-ACP synthase for possible anti-TB drug development prospects using computational tools. (9z,12z)-Octadeca-9,12-dienoic acid was isolated from Eichhornia crassipes for the first time using chromatographic techniques and identified using 1D and 2D NMR spectroscopic methods (¹H NMR, COSY, HSQC, HMBC and ¹³C NMR). The compound was then docked to β-ketoacyl-ACP synthase (KasA), an essential member of the b-ketoacyl synthases encoded in the M. tuberculosis genome in comparison with its co-crystallized ligand JSF-3285, also for the first time. (9z,12z)-Octadeca-9,12-dienoic acid interacted with only phenylalanine239 and proline201 while JSF-3285 interacted with proline201, glutamine120, alanine119, leucine116, glutamine199, histadine345, phenylalanine239, glycine240 and glycine200. (9z,12z)-Octadeca-9,12-dienoic acid had a ligand efficiency of 0.24, compared to the co-crystallized ligand's 0.36. The compound was too flexible and elongated with -4.72 KCalmol^-1 binding energy. Despite some unfavourable physico-chemical properties, the compound still provides reliable interactions that only require logical structural modifications by the addition of polar regions amongst others to increase interactions and ligand efficiency, which can consequently stand to be a better potential drug lead. For the first time, plant-based (9z,12z)-Octadeca-9,12-dienoic acid isolated from Eichhornia crassipes was shown to interact fairly well with β-ketoacyl-ACP synthase and proved to be a potential starting material from which anti-tubercular drugs can be designed.

2020-05-01·Cell Chemical Biology1区 · 生物学

A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA

1区 · 生物学

Article

作者: Ahn, Yong-Mo ; Mina, Marizel ; Ho Liang, Hsin Pin ; Kumar, Pradeep ; Capodagli, Glenn C ; Inoyama, Daigo ; Perlin, David S ; Neiditch, Matthew B ; Sukheja, Paridhi ; Freundlich, Joel S ; Park, Steven ; Li, Shao-Gang ; Grady, Courtney ; Shrestha, Riju ; Wang, Xin ; Jadhav, Ravindra ; Alland, David ; Awasthi, Divya ; Li, Liping ; Connell, Nancy ; Richmann, Todd ; Tsotetsi, Kholiswa ; Russo, Riccardo ; Zimmerman, Matthew ; Dartois, Véronique

Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis.

100 项与 JSF-3285 相关的药物交易

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