Hydrogen-Bond Donors in Drug Design

Area of Science:

• Medicinal Chemistry
• Drug Design
• Computational Chemistry

Background:

• Hydrogen-bond donors present unique challenges in drug design compared to acceptors.
• Drug-like molecules typically have more hydrogen-bond acceptors, leading to polarity imbalances.
• This imbalance impacts crucial drug properties such as permeability and aqueous solubility.

Purpose of the Study:

• To discuss the implications of polarity imbalance caused by hydrogen-bond donors and acceptors.
• To explore design opportunities arising from frustrated solvation and secondary electrostatic interactions.
• To compare different types of hydrogen-bond donors and their equivalents in drug design.

Main Methods:

• Analysis of polarity distribution in drug-like compounds.
• Discussion of solvation effects related to hydrogen-bonding.
• Comparative analysis of oxygen, nitrogen, and carbon-based hydrogen-bond donors.
• Exploration of halogen- and chalcogen-bond donors as alternatives.

Main Results:

• Hydrogen-bond donors pose greater design challenges than acceptors due to polarity imbalances.
• The presence of a hydrogen-bond donor often correlates with an acceptor, but not vice versa.
• Aligned donors and acceptors lead to frustrated solvation and secondary electrostatic interactions, offering design opportunities.

Conclusions:

• Optimizing drug permeability and solubility requires careful consideration of hydrogen-bond donor/acceptor balance.
• Exploiting frustrated solvation and electrostatic interactions can enhance ligand recognition.
• Novel hydrogen-bond donor equivalents like halogen- and chalcogen-bonds offer new design strategies.