Chemical Biology and Drug Design
Chemical Biology and Drug Design
5 years ago

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

In Silico-designed Novel Non-peptidic ABAD LD Hot Spots Mimetics Reverse Aβ-induced Mitochondrial Impairments In Vitro
Ae Nim Pae, Seo Yun Jung, TaeHun Kim, Ambily Nath Indu Viswanath, Sang Min Lim
Present work aimed to introduce non-peptidic ABAD loop D (LD) 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 LD 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 LD 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. This article is protected by copyright. All rights reserved. “In silico identification of novel inhibitors of ABAD-Aβ interaction by non-peptidic ABAD LD Hot Spots Mimetics”

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13065

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