Halting ionic shuttle to disrupt the synthetic machinery—Structural and molecular insights into the inhibitory roles of Bedaquiline towards Mycobacterium tuberculosis ATP synthase in the treatment of tuberculosis

Abstract

Therapeutic targeting of the adenosine triphosphate (ATP) machinery of Mycobacterium tuberculosis (Mtb) has recently presented a potent and alternative measure to halt the pathogenesis of tuberculosis. This has been potentiated by the development of bedaquiline (BDQ), a novel small molecule inhibitor that selectively inhibits mycobacterial F1Fo‐ATP synthase by targeting its rotor c‐ring, resulting in the disruption of ATP synthesis and consequential cell death. Although the structural resolution of the mycobacterial C9 ring in co`mplex with BDQ provided the first‐hand detail of BDQ interaction at the c‐ring region of the ATP synthase, there still remains a need to obtain essential and dynamic insights into the mechanistic activity of this drug molecule towards crucial survival machinery of Mtb. As such, for the first time, we report an atomistic model to describe the structural dynamics that explicate the experimentally reported antagonistic features of BDQ in halting ion shuttling by the mycobacterial c‐ring, using molecular dynamics simulation and the Molecular Mechanics/Poisson‐Boltzmann Surface Area methods. Results showed that BDQ exhibited a considerably high ΔG while it specifically maintained high‐affinity interactions with Glu65B and Asp32B, blocking their crucial roles in proton binding and shuttling, which is required for ATP synthesis. Moreover, the bulky nature of BDQ induced a rigid and compact conformation of the rotor c‐ring, which impedes the essential rotatory motion that drives ion exchange and shuttling. In addition, the binding affinity of a BDQ molecule was considerably increased by the complementary binding of another BDQ molecule, which indicates that an increase in BDQ molecule enhances inhibitory potency against Mtb ATP synthase. Taken together, findings provide atomistic perspectives into the inhibitory mechanisms of BDQ coupled with insights that could enhance the structure‐based design of novel ATP synthase inhibitors towards the treatment of tuberculosis.

Dual‐Knockout of Mutant Isocitrate Dehydrogenase 1 and 2 Subtypes Towards Glioma Therapy: Structural Mechanistic Insights on the Role of Vorasidenib

“…The generation of a steady‐state had confirmed that the systems performed during MD simulation were stable and hence further analysis could be performed. As seen in previous studies, a relatively high RMSD generated for a simulated system usually relates to structural instability, whereas a lower RMSD relates to a more stable system [62] . On average, m IDH1 and m IDH2 in their apo conformation revealed higher atomic deviation with RMSD values of 3.94 Å and 5.15 Å, whereas the AG‐881 bound systems of m IDH1 and m IDH2 exhibited lower RMSD values of 3.16 Å and 3.65 Å, respectively.…”

Molecular modelling of SdiA protein by selected flavonoid and terpenes compounds to attenuate virulence in Klebsiella pneumoniae

“…Notably, sabinene and genistin had the lowest RMSD averages of 1.48 Å and 1.44 Å respectively for the terpenes and flavonoids, correlating to the compounds that enacted the most structural stability. In most structural studies, a higher average RMSD correlates to a less stable structural conformation and vice versa as employed in various studies (Abdullahi et al, 2018;Salifu et al, 2019). According to (Ramírez & Caballero, 2018), RMSD < 2.0 Å corresponds to good docking solutions.…”

“…This is in reference to some of the compounds (alpha-pinene, alpha-terpinene, 3-carene, phytol, sabinene, apigenin, biacelein, genistin, phloretin and quercetin) exhibiting less flexibility on the SdiA structure while other compounds such as beta-pinene, camphene, isoterpinene, p-cymene, diadzein, fisetin and glycitein proved to be highly flexible relative to the unbound SdiA state. The substantial difference in structural flexibility of the bound terpenes and flavonoids in contrast to the unbound SdiA could play a crucial role in the biological activity of the protein (Salifu et al, 2019), as the binding of the compounds may result in a more flexible or more rigid SdiA structure which directly impacts the native state of the protein.…”

Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline

“…Furthermore, the study showed that multiple BDQ molecules can be bound to the c-ring simultaneously, depending on the drug's concentration [42]. While bound to the c-ring, interplay between BDQ molecules can occur, as suggested by the recent finding that c-ring binding affinity of a BDQ molecule is increased when there is complementary binding of an additional BDQ molecule [45].…”