In silico-designed novel non-peptidic ABAD L-D hot spot mimetics reverse A-induced mitochondrial impairments in vitro
- In silico-designed novel non-peptidic ABAD L-D hot spot mimetics reverse A-induced mitochondrial impairments in vitro
- 배애님; 임상민; 앰빌리; 김태훈; 정서윤
- Alzeheimer's disease; ABAD; virtual screening
- Issue Date
- Chemical biology & drug design
- VOL 90, NO 6-1055
- Present work aimed to introduce non-peptidic ABAD loop D (LD) hot spot 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 cross-checking 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 spot-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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