A Quantum Mechanics-Based Method to Predict Intramolecular Hydrogen Bond Formation Reflecting P-glycoprotein...

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Computational Chemistry

Background:

• Blood-brain barrier (BBB) penetration is crucial for CNS drug efficacy, governed by passive permeability and active transport.
• P-glycoprotein (P-gp) is a key efflux transporter limiting BBB penetration.
• Intramolecular hydrogen bonding (IMHB) is a strategy to enhance passive permeability and reduce P-gp recognition.

Purpose of the Study:

• To investigate the impact of intramolecular hydrogen bonding formation ratios (IMHBRs) on P-gp recognition.
• To develop a quantum-mechanics-based method for predicting IMHBRs.
• To assess the broader applicability of the IMHBR prediction method for drug design.

Main Methods:

• Utilized quantum mechanics to develop a predictive method for IMHB formation ratios (IMHBRs).
• Correlated predicted IMHBRs with experimentally measured temperature coefficients from NMR.
• Evaluated the correlation between IMHBRs and P-gp efflux ratios for drug candidates.

Main Results:

• Predicted IMHBRs accurately reflected experimental NMR data.
• IMHBRs showed a strong correlation with P-gp efflux ratios, indicating their role in transporter recognition.
• The IMHBR prediction method was successfully applied to hNK2 receptor antagonists.

Conclusions:

• IMHB formation propensity is a critical factor influencing P-gp recognition and BBB penetration.
• The developed quantum-mechanics-based method provides a valuable tool for predicting IMHBRs.
• This predictive approach can guide the design of novel brain-penetrant therapeutics targeting various receptors.