title: QM methods in structure based design: utility in probing protein-ligand interactions.
abstract: Small changes in ligand structure can lead to large unexpected changes in activity yet it is often not possible to rationalize these effects using empirical modeling techniques, suggesting more effective methods are required. In this study we investigate the use of high level QM methods to study the interactions found within protein-ligand complexes as improved understanding of these could help in the design of new, more active molecules. We study aspects of ligand binding in a set of protein ligand complexes containing ligand efficient, fragment-like inhibitors as these structures are often challenging to determine experimentally. To assess the reliability of our theoretical models we compare the MP2/6-31+G** QM results to the original X-ray coordinates and to QM/MM B3LYP/6-31G*//UFF results which we have previously reported. We also contrast these results with data obtained from an analysis of the distribution of comparable interactions found in (a) high resolution kinase complexes (≤ 1.8Å) from the PDB and (b) more generic, small molecule crystal structures from the CSD.
authors.affiliation: Department of Chemistry, Faculty of Science, Kasetsart University, 50 Phaholyothin Rd, Chatuchak, Bangkok 10900, Thailand. paul.gleeson@ku.ac.th
authors.forename: M Paul
authors.initials: MP
authors.lastname: Gleeson
authors.forename: Supa
authors.initials: S
authors.lastname: Hannongbua
authors.forename: Duangkamol
authors.initials: D
authors.lastname: Gleeson
mesh_terms: D018360:Crystallography, X-Ray; D030562:Databases, Protein; D015195:Drug Design; D006860:Hydrogen Bonding / Q000187:drug effects; D008024:Ligands; D055595:Mechanical Phenomena / Q000187:drug effects; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011789:Quantum Theory; D015203:Reproducibility of Results
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases