Broadening the horizon: Integrative pharmacophore-based and cheminformatics screening of novel chemical modulators of mitochondria ATP synthase towards interventive Alzheimer's disease therapy.

The proven efficacy of J147 in the treatment of Alzheimer's disease (AD) has been emphatic, particularly since its selective modulatory roles towards mitochondrial ATP synthase (mATPase) were defined. This prospect, if methodically probed, could further pave way for the discovery of novel anti-AD drugs with improved pharmacokinetics and therapeutic potential. To this effect, for the first time, we employed a four-step paradigm that integrated our in-house per-residue energy decomposition (PRED) protocol coupled with molecular dynamics, cheminformatics and analytical binding free energy methods. This was geared towards the screening and identification of new leads that exhibit modulatory potentials towards mATPase in a J147-similar pattern. Interestingly, from a large-scale library of compounds, we funnelled down on three potential hits that demonstrated selective and high-affinity binding activities towards α-F1-ATP synthase (ATP5A) relative to J147. Moreover, these compounds exhibited higher binding propensity with a differential ΔGs greater than -1 kcal/mol comparative to J147, and also elicited distinct modulatory effects on ATP5A domain structures. More interestingly, per-residue pharmacophore modeling of these lead compounds revealed similar interactive patterns with crucial residues at the α-site region of ATP5A characterized by high energy contributions based on binding complementarity. Recurrent target residues involved in high-affinity interactions with the hit molecules relative to J147 include Arg1112 and Gln426. Furthermore, assessments of pharmacokinetics revealed that the lead compounds were highly drug-like with minimal violations of the Lipinski's rule of five. As developed in this study, the most extrapolative pharmacophore model of the selected hits encompassed three electron donors and one electron acceptor. We speculate that these findings will be fundamental to the reformation of anti-AD drug discovery procedures.