用药效团引导扩散模型生成高亲和力候选药物分子
Pharmacophore-guided de novo drug design with diffusion bridge
- 基于药效团空间结构，通过SE(3)等变扩散桥生成分子
- 生成分子对目标蛋白结合亲和力高，命中率优异
- 适合需精准控制生物活性特征的药物设计场景
从头设计具有特定生物活性的药物分子是药物发现中的关键挑战。现有方法多依赖靶标蛋白口袋结构来引导分子生成，但口袋区域常包含与配体无直接作用的冗余原子。本文提出PharmacoBridge，一种药效团引导的从头药物设计方法，利用扩散桥在SE(3)-等变变换下将药效团的空间排列转化为分子结构，实现对生成分子上关键生化特征位置的精细控制。实验表明，该方法能生成与潜在靶蛋白具有高结合亲和力的命中候选分子。
原文摘要 · Abstract (English)
De novo design of bioactive drug molecules with potential to treat desired biological targets is a profound task in the drug discovery process. Existing approaches tend to leverage the pocket structure of the target protein to condition the molecule generation. However, even the pocket area of the target protein may contain redundant information since not all atoms in the pocket is responsible for the interaction with the ligand. In this work, we propose PharmacoBridge, a phamacophore-guided de novo design approach to generate drug candidates inducing desired bioactivity via diffusion bridge. Our method adapts the diffusion bridge to effectively convert pharmacophore arrangements in the spatial space into molecular structures under the manner of SE(3)-equivariant transformation, providing sophisticated control over optimal biochemical feature arrangements on the generated molecules. PharmacoBridge is demonstrated to generate hit candidates that exhibit high binding affinity with potential protein targets.
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