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

Area of Science:

• Computational chemistry
• Drug discovery
• Pharmacokinetics

Background:

• Optimizing molecular properties like permeability and P-glycoprotein (P-gp) efflux is crucial in drug discovery.
• Modulating intrinsic hydrogen bond strength (HBS) is an effective strategy for this optimization.
• Current Quantum Mechanics (QM) based HBS calculations are computationally intensive for large molecule sets.

Purpose of the Study:

• To develop a high-throughput method for calculating molecular intrinsic HBS.
• To enable efficient optimization of drug permeability and P-gp efflux.

Main Methods:

• Introduction of a fragment-based high-throughput HBS calculation approach.
• Validation of the method using internal and external datasets.

Main Results:

• Demonstrated optimization of P-gp efflux and permeability by modulating calculated HBS.
• Successful application of the fragment-based method for HBS estimation.

Conclusions:

• The developed method allows medicinal chemists to calculate HBS rapidly.
• This facilitates improved efficiency in balancing multiple properties during drug discovery.
• Accelerates the optimization of permeability and P-gp efflux for drug candidates.