The role of hydrogen-bonds in drug binding

Prog Clin Biol Res. 1989;289:433-44.

Abstract

Hydrogen-bonds play a crucial role in determining the specificity of ligand binding. Their important contribution is explicitly incorporated into a computational method, called GRID, which has been designed to detect energetically favourable ligand binding sites on a chosen target molecule of known structure. An empirical energy function consisting of a Lennard-Jones, an electrostatic and a hydrogen-bonding term is employed. The latter term is found to be necessary because spherically symmetric atom-centred forces alone may not adequately reproduce the geometry of two interacting molecules. The hydrogen-bonding term is dependent on the length and orientation of the hydrogen-bond. Its functional form also varies according to the chemical nature of both the hydrogen-bond donor and acceptor atoms, and has been modelled to fit experimental observations of crystal structures. The mobility of the hydrogen-bonding hydrogens is considered analytically in calculating the hydrogen-bond energy. The hydrogen-bonding energy functions will be described and their application will be demonstrated on molecules of pharmacological interest where hydrogen-bonds influence the binding of ligands.

MeSH terms

  • Camphor 5-Monooxygenase
  • Catecholamines / metabolism
  • Chemical Phenomena
  • Chemistry, Physical*
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Design
  • Histidine / metabolism
  • Hydrogen Bonding*
  • Ligands
  • Mathematical Computing
  • Mixed Function Oxygenases / metabolism
  • Pharmaceutical Preparations / metabolism*
  • Protein Binding*
  • Receptors, Drug / metabolism*
  • Thermodynamics

Substances

  • Catecholamines
  • Ligands
  • Pharmaceutical Preparations
  • Receptors, Drug
  • Histidine
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Camphor 5-Monooxygenase