In silico-designed novel non-peptidic ABAD L-D hot spot mimetics reverse A-induced mitochondrial impairments in vitro

Abstract

Present work aimed to introduce non-peptidic ABAD loop D (L-D) hot spot mimetics as ABAD-A inhibitors. A full-length atomistic model of ABAD-A complex was built as a scaffold to launch the lead design and its topology later verified by cross-checking the computational mutagenesis results with that of in vitro data. Thereafter, the interactions of prime A-binding L-D residuesTyr101, Thr108, and Thr110were translated into specific pharmacophore features and this hypothesis subsequently used as a virtual screen query. ELISA-based screening of 20 hits identified two promising lead candidates, VC15 and VC19 with an IC50 of 4.4 +/- 0.3 and 9.6 +/- 0.1m, respectively. They productively reversed A-induced mitochondrial dysfunctions such as mitochondrial membrane potential loss (JC-1 assay), toxicity (MTT assay), and ATP reduction (ATP assay) in addition to increased cell viabilities. This is the first reporting of L-D hot spot-centric in silico scheme to discover novel compounds with promising ABAD-A inhibitory potential. These chemotypes are proposed for further structural optimization to derive novel Alzheimer's disease (AD) therapeutics.