In Silico-designed Novel Non-peptidic ABAD LD Hot Spots Mimetics Reverse Aβ-induced Mitochondrial Impairments In Vitro

Abstract

Present work aimed to introduce non-peptidic ABAD loop D (L_D) hot spots mimetics as ABAD-Aβ inhibitors. A full length atomistic model of ABAD-Aβ complex was built as a scaffold to launch the lead design and its topology later verified by crosschecking the computational mutagenesis results with that of in vitro data. Thereafter, the interactions of prime Aβ-binding L_D residues- Tyr101, Thr108, and Thr110 were 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±0.1 μM respectively. They productively reversed Aβ-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 spots-centric in silico scheme to discover novel compounds with promising ABAD-Aβ inhibitory potential. These chemotypes are proposed for further structural optimization to derive novel Alzheimer's disease (AD) therapeutics.

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"In silico identification of novel inhibitors of ABAD-Aβ interaction by non-peptidic ABAD LD Hot Spots Mimetics"

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