title: The role of hydrogen-bonds in drug binding.
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.
authors.affiliation: University of Oxford, Laboratory of Molecular, Biophysics.
authors.forename: R C
authors.initials: RC
authors.lastname: Wade
authors.forename: P J
authors.initials: PJ
authors.lastname: Goodford
mesh_terms: D019475:Camphor 5-Monooxygenase; D002395:Catecholamines / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D006639:Histidine / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D008432:Mathematical Computing; D006899:Mixed Function Oxygenases / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D011955:Receptors, Drug / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D002395:Catecholamines; D008024:Ligands; D004364:Pharmaceutical Preparations; D011955:Receptors, Drug; D006639:Histidine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019475:Camphor 5-Monooxygenase