Mixture-of-Experts Based Dissociation Kinetic Model for <i>De Novo</i> Design of HSP90 Inhibitors with Prolonged Residence Time

The dissociation rate constant (<i>k</i>_off) significantly impacts the drug potency and dosing frequency. This work proposes a powerful optimization-based framework for <i>de novo</i> drug design guided by <i>k</i>_off. First, a comprehensive database containing 2,773 unique <i>k</i>_off values is created. Based on the database, a novel generic dissociation kinetic model is developed with a mixture-of-experts architecture, enabling high-throughput predictions of <i>k</i>_off with high accuracy. The developed model is then integrated with an optimization-based mathematical programming approach to design drug candidates with low <i>k</i>_off. Finally, the τ-RAMD method is utilized to rigorously verify the designed potential drug candidates. In a case study, the framework successfully identified numerous new potential HSP90 inhibitor candidates, achieving a maximum 45.7% improvement in residence time (τ = 1/<i>k</i>_off) compared to that of a known exceptional HSP90 inhibitor. These findings demonstrate the feasibility and effectiveness of the kinetics-guided optimization-based <i>de novo</i> drug design framework in designing drug candidates with prolonged τ.