Deep Geometry Handling and Fragment-wise Molecular 3D Graph Generation

TL;DR

This paper introduces FragGen, a novel fragment-wise molecular generation method that enhances geometric accuracy and synthesizability, validated by designing potent kinase inhibitors.

Contribution

The paper proposes a new hybrid strategy and the FragGen method, improving geometry reliability and synthesis accessibility in fragment-wise molecular generation.

Findings

FragGen produces more accurate molecular geometries.

It enables the design of molecules with nanomolar potency.

FragGen outperforms existing methods in geometry and synthesis accessibility.

Abstract

Most earlier 3D structure-based molecular generation approaches follow an atom-wise paradigm, incrementally adding atoms to a partially built molecular fragment within protein pockets. These methods, while effective in designing tightly bound ligands, often overlook other essential properties such as synthesizability. The fragment-wise generation paradigm offers a promising solution. However, a common challenge across both atom-wise and fragment-wise methods lies in their limited ability to co-design plausible chemical and geometrical structures, resulting in distorted conformations. In response to this challenge, we introduce the Deep Geometry Handling protocol, a more abstract design that extends the design focus beyond the model architecture. Through a comprehensive review of existing geometry-related models and their protocols, we propose a novel hybrid strategy, culminating in the development of FragGen - a geometry-reliable, fragment-wise molecular generation method. FragGen marks a significant leap forward in the quality of generated geometry and the synthesis accessibility of molecules. The efficacy of FragGen is further validated by its successful application in designing type II kinase inhibitors at the nanomolar level.