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Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors.

ABSTRACT: The treatment options for a patient diagnosed with Alzheimer's disease (AD) are currently limited. The cerebral accumulation of amyloid-? (A?) is a critical molecular event in the pathogenesis of AD. When the amyloidogenic ?-secretase (BACE1) is inhibited, the production of A? peptide is reduced. Henceforth, the main goal of this study is the discovery of new small bioactive molecules that potentially reach the brain and inhibit BACE1. The work was conducted by a customized molecular modelling protocol, including pharmacophore-based and molecular docking-based virtual screening (VS). Structure-based (SB) and ligand-based (LB) pharmacophore models were designed to accurately screen several drug-like compound databases. The retrieved hits were subjected to molecular docking and in silico filtered to predict their ability to cross the blood-brain barrier (BBB). Additionally, 34 high-scoring compounds structurally distinct from known BACE1 inhibitors were selected for in vitro screening assay, which resulted in 13 novel hit-compounds for this relevant therapeutic target. This study disclosed new BACE1 inhibitors, proving the utility of combining computational and in vitro approaches for effectively predicting anti-BACE1 agents in the early drug discovery process.

SUBMITTER: Coimbra JRM

PROVIDER: S-EPMC7226079 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors.

Coimbra Judite R M JRM Baptista Salete J SJ Dinis Teresa C P TCP Silva Maria M C MMC Moreira Paula I PI Santos Armanda E AE Salvador Jorge A R JAR

Biomolecules 20200401 4

The treatment options for a patient diagnosed with Alzheimer's disease (AD) are currently limited. The cerebral accumulation of amyloid-β (Aβ) is a critical molecular event in the pathogenesis of AD. When the amyloidogenic β-secretase (BACE1) is inhibited, the production of Aβ peptide is reduced. Henceforth, the main goal of this study is the discovery of new small bioactive molecules that potentially reach the brain and inhibit BACE1. The work was conducted by a customized molecular modelling p ...[more]

PMID: 32244832

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Project description:IntroductionPhosphoinositide 3-kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of various diseases, and the diverse physiological roles of class I PI3K isoforms (α, β, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. However, the high structural conservation among the PI3K family makes it a big challenge to develop selective PI3Kγ inhibitors.ObjectivesA novel machine learning-based virtual screening with multiple PI3Kγ protein structures was developed to discover novel PI3Kγ inhibitors.MethodsA large chemical database was screened using the virtual screening model, the top-ranked compounds were then subjected to a series of bio-evaluations, which led to the discovery of JN-KI3. The selective inhibition mechanism of JN-KI3 against PI3Kγ was uncovered by a theoretical study.Results49 hits were identified through virtual screening, and the cell-free enzymatic studies found that JN-KI3 selectively inhibited PI3Kγ at a concentration as low as 3,873 nM but had no inhibitory effect on Class IA PI3Ks, leading to the selective cytotoxicity on hematologic cancer cells. Meanwhile, JN-KI3 potently blocked the PI3K signaling, finally led to distinct apoptosis of hematologic cell lines at a low concentration. Lastly, the key residues of PI3Kγ and the structural characteristics of JN-KI3, which both would influence γ isoform-selective inhibition, were highlighted by systematic theoretical studies.ConclusionThe developed virtual screening model strongly manifests the robustness to find novel PI3Kγ inhibitors. JN-KI3 displays a specific cytotoxicity on hematologic tumor cells, and significantly promotes apoptosis associated with the inhibition of the PI3K signaling, which depicts PI3Kγ as a potential target for the hematologic tumor therapy. The theoretical results reveal that those key residues interacting with JN-KI3 are less common compared to most of the reported PI3Kγ inhibitors, indicating that JN-KI3 has novel structural characteristics as a selective PIK3γ inhibitor.

Dataset Information

Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors.

Publications

Combining Virtual Screening Protocol and In Vitro Evaluation towards the Discovery of BACE1 Inhibitors.

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