title: The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors.
abstract: We have determined the effects that tightly bound water molecules have on the de novo design of cyclin-dependent kinase-2 (CDK2) ligands. In particular, we have analyzed the impact of a specific structural water molecule on the chemical diversity and binding mode of ligands generated through a de novo structure-based ligand generation method in the binding site of CDK2. The tightly bound water molecule modifies the size and shape of the binding site and we have found that it also imposed constraints on the observed binding modes of the generated ligands. This in turn had the indirect effect of reducing the chemical diversity of the underlying molecular scaffolds that were able to bind to the enzyme satisfactorily. [Figure: see text].
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK. atgs@cantab.net
authors.forename: Alfonso T
authors.initials: AT
authors.lastname: García-Sosa
authors.forename: Ricardo L
authors.initials: RL
authors.lastname: Mancera
mesh_terms: D001665:Binding Sites; D017076:Computer-Aided Design; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000145:classification; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry*
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D014867:Water; D051357:Cyclin-Dependent Kinase 2