title: Combinatorial ligand design targeted at protein families.
abstract: We describe a method to create ligands specific for a given protein family. The method is applied to generate ligand candidates for the cyclin-dependent kinase (CDK) family. The CDK family of proteins is involved in regulating the cell cycle by alternately activating and deactivating the cell's progression through the cycle. CDKs are activated by association with cyclin and are inhibited by complexation with small molecules. X-ray crystal structures are available for three of the thirteen known CDK family members: CDK2, CDK5 and CDK 6. In this work, we use novel computational approaches to design ligand candidates that are potentially inhibitory across the three CDK family members as well as more specific molecules which can potentially inhibit one or any combination of two of the three CDK family members. We define a new scoring term, SpecScore, to quantify the potential inhibitory power of the generated structures. According to a search of the World Drug Alerts, the highest scoring SpecScore molecule that is specific for the three CDK family members shows very similar chemical characteristics and functional groups to numerous molecules known to deactivate several members of the CDK family.
authors.affiliation: De Novo Pharmaceuticals Ltd., Vision Park, Histon, Cambridge CB4 9ZR, U.K. nikolay.todorov@denovopharma.com
authors.forename: Nikolay P
authors.initials: NP
authors.lastname: Todorov
authors.forename: Christoph L
authors.initials: CL
authors.lastname: Buenemann
authors.forename: Ian L
authors.initials: IL
authors.lastname: Alberts
mesh_terms: D020650:Combinatorial Chemistry Techniques; D018844:Cyclin-Dependent Kinases / Q000737:chemistry* / Q000145:classification / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D008024:Ligands; D018844:Cyclin-Dependent Kinases