Integrating structure-guided and fragment-based inhibitor design to combat bedaquiline resistant Mycobacterium tuberculosis: a molecular dynamics study

The first FDA approved, MDR-TB inhibitory drug bedaquiline (BDQ), entraps the c-ring of the proton-translocating F₀ region of enzyme ATP synthase of Mycobacterium tuberculosis, thus obstructing successive ATP production. Present-day BDQ-resistance has been associated with cardiotoxicity and mutation(s) in the atpE gene encoding the c subunit of ATP synthase (ATPc) generating five distinct ATPc mutants: Ala63→Pro, Ile66→Met, Asp28→Gly, Asp28→Val and Glu61→Asp. We created three discrete libraries, first by repurposing bedaquiline via scaffold hopping approach, second one having natural plant compounds and the third being experimentally derived analogues of BDQ to identify one drug candidate that can inhibit ATPc activity more efficiently with less toxic properties. For this purpose, we adopted techniques like molecular dynamics simulation, virtual screening, PCA, DCCM, binding affinity analysis to gauge structure-function relationship of the L136-ATPc complexes. L136 was found to induce a distinguishable conformational change in the bound ATPc which captivated the c₉ rotor ring. L136 displays a binding free energy of -57.294, -59.027, -57.273, -58.726, -55.889 and -58.651 kcal/mol for ATPc_WT and the five respective mutants. The pIC₅₀ value for the L136 ligand for the same proteins was unveiled to be 6.760, 7.285, 6.898, 7.222, 6.987 and 7.687. Moreover, L136 exhibited a strong ADMET profile. Furthermore, we discovered that the change in the hydrophobic platform in ATPc mutants hinders BDQ binding, which is overcome by L136, ensuring efficient binding and providing an assessment of L136's mechanism of ATPc inhibition. L136 provides a scope for in vivo test for future clinical drug trials.