Yao Zhou, Zhipei Sang, Chao Xu, Ze Cao, Kaixiang Xiao, Qian Jia, Yutao He, Haibin Luo, Shuheng Huang
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引用次数: 0
Abstract
Lead optimization is a crucial step in drug design. Generative AI-driven molecular modification has emerged as a powerful strategy to accelerate lead optimization by efficiently exploring chemical space and enhancing key drug-like properties. However, current AI tools primarily focus on de novo scaffold design rather than targeted modifications of validated lead compounds, limiting their practical utility in medicinal chemistry. Herein, we developed MolMod ( http://software.tdd-lab.com/molmod ), a web-based platform that enables site-specific molecular modifications through fragment-based optimization. MolMod employs a transformer model trained on 8.3 million ZINC20 compounds and fine-tuned with ~30,000 medicinal chemistry fragments from ChEMBL. Users mark specific modification sites on their molecules, and the model generates property-optimized fragments for these positions. The platform achieves high scaffold retention while maintaining a ≥99.99% fragment assembly success rate across extensive validation tests. Single-property optimization achieved >93% success rates, while multi-property constraints maintained 95% accuracy. Experimental validation confirmed the platform's accuracy: optimization of α-mangostin increased aqueous solubility from <5 μg/mL to 789 μg/mL through single-site modification, closely matching computational predictions (LogS: -6.128 to -3.829). MolMod provides ADMET profiles for all generated molecules and enables real-time visualization of structural modifications. By focusing on site-specific modifications rather than de novo generation, MolMod aligns with medicinal chemistry workflows and provides a practical tool for both computational and experimental scientists.
期刊介绍:
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;