A structure-based framework for selective inhibitor design and optimization

Abstract Structure-based drug design aims to create active compounds with favorable properties by analyzing target structures. Recently, deep generative models have facilitated structure-specific molecular generation. However, many methods are limited by inadequate pharmaceutical data, resulting in suboptimal molecular properties and unstable conformations. Additionally, these approaches often overlook binding pocket interactions and struggle with selective inhibitor design. To address these challenges, we developed a framework called Coarse-grained and Multi-dimensional Data-driven molecular generation (CMD-GEN). CMD-GEN bridges ligand-protein complexes with drug-like molecules by utilizing coarse-grained pharmacophore points sampled from diffusion model, enriching training data. Through a hierarchical architecture, it decomposes three-dimensional molecule generation within the pocket into pharmacophore point sampling, chemical structure generation, and conformation alignment, mitigating instability issues. CMD-GEN outperforms other methods in benchmark tests and controls drug-likeness effectively. Furthermore, CMD-GEN excels in cases across three synthetic lethal targets, and wet-lab validation with PARP1/2 inhibitors confirms its potential in selective inhibitor design.