In Silico Discovery of β-Secretase Inhibitors

Abstract

Alzheimer's disease, the most common amyloid-associated disorder, accounts for the majority of the dementia diagnosed after the age of 60. The cleavage of the beta-amyloid precursor protein is initiated by beta-secretase (BACE-1), a membrane-bound aspartic protease, which has emerged as an important but difficult protein target. Here, an in silico screening approach consisting of fragment-based docking, ligand conformational search by a genetic algorithm, and evaluation of free energy of binding was used to identify low-molecular-weight inhibitors of BACE-1. More than 300,000 small molecules were docked and about 15,000 prioritized according to a linear interaction energy model with evaluation of solvation by continuum electrostatics. Eighty-eight compounds were tested in vitro, and 10 of them showed an IC(50) value lower than 100 microM in a BACE-1 enzymatic assay. Interestingly, the 10 active compounds shared a triazine scaffold. Moreover, four of them were active in an assay with mammalian cells (EC(50) < 20 microM), indicating that they are cell-permeable. Therefore, these triazine derivatives are very promising lead candidates for BACE-1 inhibition. The discoveries of this series and two other series of nonpeptidic BACE-1 inhibitors demonstrate the usefulness of our in silico high-throughput screening approach.

Structure-based Discovery of Antagonists of Nuclear Receptor LRH-1

“…We attribute the success in the discovery of LRH-1-specific inhibitors to an efficient screening strategy, which combined high throughput computer-assisted search for compounds with preferred structural characteristics with the following in vitro direct binding and functional assays for compound selection and validation. Such combinations of the protein-centric computational approaches with experimental verifications of the top-ranked hits have proven to be successful for identification of specific ligands for different protein targets in the past (53)(54)(55)(56)(57).…”

Discovery of Plasmepsin Inhibitors by Fragment‐Based Docking and Consensus Scoring

“…High-throughput fragment-based docking was carried out using the methods described in [11]. Briefly, fragments were docked to the binding site using the computer program SEED [25,35] which takes into account electrostatic solvation effects by a generalized Born approach based on numerical evaluation of Born radii [36].…”

“…A similar in silico fragment-based approach had been used previously to identify novel inhibitors of the aspartic protease β-secretase [10,11], two kinases [12,13], and a flaviviral serine protease [14]. The major difference between our previous in silico screening campaigns and the one reported here is the final scoring of the poses.…”

A double‐headed cathepsin B inhibitor devoid of warhead

“…Molecules with more than nine rotatable bonds were neglected. The resulting 48,026 cluster representatives were docked as in previous in silico campaigns (Huang et al 2005(Huang et al , 2006Kolb et al 2008). For each molecule docked by the program FFLD (Fragment-based Flexible Ligand Docking) (Budin et al 2001;Cecchini et al 2004), the 300 most favorable poses were clustered with the leader algorithm yielding 764,776 poses (;17 poses per compound, 44,527 compounds).…”