High-throughput hydrogen bond strength calculation and its applications in optimizing drug ADME properties

Abstract

Aim: Modifying the molecule's intrinsic hydrogen bond strength (HBS) is a useful approach in optimizing its permeability and P-glycoprotein (P-gp) efflux. Quantum mechanics (QM) based computation has been utilized to estimate the molecular intrinsic HBS. Despite its usefulness, the computation is time consuming for a large set of molecules. Methodology/results: We introduced a fragment-based high-throughput HBS calculation method and validated it with internal and external datasets. Examples have been presented where the P-gp efflux and permeability can be optimized by modulating calculated HBS. Conclusion: The results will enable medicinal chemists to calculate HBS in a high-throughput manner while optimizing permeability and P-gp efflux. This will further improve the efficiency of balancing multiple properties during drug discovery process.