Molecule generation for target protein binding with hierarchical consistency diffusion model

Abstract

Effective generation of molecular structures that bind to target proteins is crucial for lead identification and optimization in drug discovery. Despite advancements in atom- and motif-wise models for 3D molecular generation, current methods often struggle with validity and reliability. To address these issues, we develop the Atom-Motif Consistency Diffusion Model (AMDiff), utilizing a joint-training paradigm for multi-view learning. This model features a hierarchical diffusion architecture that integrates both atom- and motif-views of molecules, allowing for comprehensive exploration of complementary information. By leveraging classifier-free guidance and incorporating topological features as conditional inputs, AMDiff ensures robust molecule generation across diverse targets. Compared to existing approaches, AMDiff exhibits superior validity and novelty in generating molecules tailored to fit various protein pockets. Case studies targeting protein kinases, including Anaplastic Lymphoma Kinase (ALK) and Cyclin-dependent kinase 4 (CDK4), demonstrate the capability in structure-based de novo drug design. Overall, AMDiff bridges the gap between atom-view and motif-view drug discovery and accelerating the development of target-specific molecules.