title: De novo ligand design to partially flexible active sites: application of the ReFlex algorithm to carboxypeptidase A, acetylcholinesterase, and the estrogen receptor.
abstract: Reflex is a recent algorithm in the de novo ligand design software, SkelGen, that allows the flexibility of amino acid side chains in a protein to be taken into account during the drug-design process. In this paper the impact of flexibility on the solutions generated by the de novo design algorithm, when applied to carboxypeptidase A, acetylcholinesterase, and the estrogen receptor (ER), is investigated. The results for each of the targets indicate that when allowing side-chain movement in the active site, solutions are generated that were not accessible from the multiple static protein conformations available for these targets. Furthermore, an analysis of structures generated in a flexible versus a static ER active site suggests that these additional solutions are not merely noise but contain many interesting chemotypes.
authors.affiliation: De Novo Pharmaceuticals Ltd., Compass House, Vision Park, Chivers Way, Histon, Cambridge, United Kingdom CB24 9ZR. stuart.firth-clark@denovopharma.com
authors.forename: Stuart
authors.initials: S
authors.lastname: Firth-Clark
authors.forename: Stewart B
authors.initials: SB
authors.lastname: Kirton
authors.forename: Henriëtte M G
authors.initials: HM
authors.lastname: Willems
authors.forename: Anthony
authors.initials: A
authors.lastname: Williams
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000465:Algorithms; D001665:Binding Sites; D043422:Carboxypeptidases A / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D009038:Motion; D018583:Pliability; D011487:Protein Conformation; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011960:Receptors, Estrogen; D000110:Acetylcholinesterase; D043422:Carboxypeptidases A