Physicochemical and Structural Determinants of BACE1-Selective Inhibition: An Integrative Modeling Study using A Combined Ligand-and Structure-Based Approach
Year: 2026
Type: preprint
Abstract: BACE1 constitutes a primary therapeutic target for Alzheimer's disease, yet clinical advancement is impeded by the structural homology shared with its closest homolog BACE2 or other aspartyl proteases, often leading to off-target inhibition.Here, an integrative modeling framework deciphered the molecular determinants of binding selectivity using 76 nphenylpicolinamide derivatives with experimentally determined potencies.Ligand-based Quantitative Structure-Activity Relationship (QSAR) models for BACE1 potency, BACE2 potency, and BACE1/BACE2 selectivity were developed via Genetic Algorithm-optimized Multiple Linear Regression.The resulting equations exhibited robust predictive performance, with the selectivity model identifying molecular dipole moments and hydrophobicity as decisive physicochemical features.Complementarily, a structure-based approach quantified protein-ligand interactions through a novel contact occupancy metric, analyzed via Principal Component Analysis and Ordinary Least Squares regression.Subsite SS9 emerged as the predominant driver of selectivity through the involvement of Gly11 and Ala335 as critical residues, while Tyr71, Val69, and Thr231 were identified as significant contributors from distinct subsites.These structural insights rationalize the QSAR descriptors, linking dipole moments to the electrostatic environment around Tyr71 and hydrophobicity to the non-polar character of SS9.Collectively, this synergistic strategy bridges ligand-derived physicochemical properties with structure-derived intermolecular contacts, offering a validated pathway for the identification of target residues as selectivity drivers.
Source: ChemRxiv
Institutions: Centre National de la Recherche Scientifique, Inserm, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris Sciences et Lettres, Université Paris-Saclay, Institut de Biologie Intégrative de la Cellule, Institut Curie, École Polytechnique, Laboratoire d'Informatique de l'École Polytechnique, University of Havana
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
Funder: Fondation Vaincre Alzheimer
OpenAlex ID: W7167495734