CReM-dock: de novo design of synthetically feasible structures guided by molecular docking

Abstract

The de novo generation of chemical compounds represents a compelling strategy for the exploration of a significantly broader chemical space compared to traditional virtual screening methods. However, fragment-based approaches often encounter challenges related to the low synthetic accessibility of generated structures. In this study, we integrated the previously established fragment-based structure generator, CReM, with molecular docking techniques implemented in EasyDock to facilitate the exploration of chemical space. This novel methodology enables indirect control over the synthetic accessibility and diversity of the generated structures, enhances an objective function to yield compounds with desirable physicochemical properties, and maintains key protein–ligand interactions and ligand conformations. The structures generated through this approach exhibited a high degree of novelty and demonstrated competitiveness with those produced by leading methodologies in the field, as demonstrated by Absolute Binding Free Energy calculations. We illustrated the versatility of the developed approach through several case studies, showcasing its applicability to both de novo generation and fragment expansion tasks. The tool developed in this study is open-source and can be accessed at https://github.com/ci-lab-cz/crem-dock.