DOI: 10.1002/minf.201000143 Structural Bioinformatics Approach of Cyclin-Dependent Kinases 1 and 3 Complexed with Inhibitors Lucas A. Saraiva,* [a] Marcia P. Veloso, [a] I. Camps, [b] and Nelson J. F. da Silveira [b] Presented at the 18th European Symposium on Quantitative Structure Activity Relationships, EuroQSAR 2010, Rhodes, Greece 1 Introduction The mammalian cell progression cycle has been well estab- lished to be tightly controlled by the activity of cyclin-de- pendent kinases (CDKs). [1] Therefore protein kinases play a key role in various cellular processes such as cell prolifera- tion, differentiation, and survival. [2,3] CDKs are inactive as monomers, so that, their activity requires binding of regula- tory subunits known as cyclin, a protein whose concentra- tion fluctuates during cell cycle, and reversible phosphory- lation reactions by CDK-activating kinase (CAK) on a specific threonine residue. [4,5] An additional level of regulation is provided by several negative regulatory proteins known as CDKs inhibitors (CKIs). [6] In eukaryotes, cell cycle progres- sion is modulated by the continuous and intermittent acti- vation of cyclin/CDKs. Deregulation of the cell cycle is con- nected with cancer promotion. [7] Furthermore, CDKs also participate in various other cellular processes, such as me- tabolism, transcription (CDK7-CDK9), apoptosis (CDK2) and neural development (CDK5). [8] Mutations which might de- regulate the kinases’ activity or expression, or even both, would lead to the emergence of several diseases, such as neurodegenerative disorders (Alzheimer’s [9] , Parkinson’s [10] and in ischemia [11] ), renal diseases (such as polycystic kidney disease) [12] , pain signalling [13] , inflammatory re- sponse [14] and viral infections. [15] CDK1, also nominated as cell division control protein 2 (cdc2), has been long time regarded as the major modula- tor of mitosis. [16] A previous study accomplished with CDK inhibitors demonstrated that CDK1 inhibition may have prominent therapeutic results in cells transformed by MYC gene, but not induced by other oncogenes. When treated with Purvalanol, a CDK inhibitor with specificity for CDK1, CDK2 and CDK5, MYC-induced lymphomas and hepatoblas- tomas quickly go through apoptosis. Thus, CDK1 inhibition may result in substantial therapeutic benefits in human tu- mours which super express MYC gene. [17] Furthermore, a current research indicated that transitory inhibition of MYC, selectively kills mouse lung cancer cells, entailing it in an attractive cancer drug target. [18] Current studies have being shown a novel complex: CDK3-cyclin C. In early G1 phase, it is noticed its first activi- ty [19] , which attains an apex in mid G1 [20] . Transfection of a dominant-negative mutant of CDK3 induces a G1 arrest, which could not be rescued by CDK2. This fact implies that CDK3 plays an important role for G1/S transition in the mammalian cell cycle, which is unlike from the activity of CDK2. [21] It has also been shown that overexpression of [a] L. A. Saraiva, M. P. Veloso Faculty of Pharmaceutical Science Rua Gabriel Monteiro da Silva, 700 Centro – Alfenas/MG Postal Code: 37130000, Brazil. tel: + 553133322556 *e-mail: lucasandrade_22@yahoo.com.br [b] I. Camps, N. J. F. d. Silveira Institute of Exacts Science Rua Gabriel Monteiro da Silva, 700 Centro – Alfenas/MG Postal Code: 37130000, Brazil. Abstract : The cyclin-dependent kinases or CDKs participate in the regulation of both the cell progression cycle and the RNA polymerase-II transcription cycle. In several human tu- mours deregulation of CDK-related mechanisms have been detected, e.g., overexpression of cyclins or deletion of genes encoding for CKIs. Regarding these observations, CDKs came up to be interesting targets for elaboration of novel antitumour drugs. Based on the importance of the CDKs, this research aimed to describe, to characterize and to compare the molecular models of CDK1 and CDK3. Since the structures of human CDK1 and CDK3 are unavailable in the Protein Data Bank –PDB, homology models were creat- ed based on the CDK2 as the template, once they share a substantial identity. The structural studies of the CDK1 and CDK3 biding sites were conducted by molecular docking with 15 different CDK inhibitors previously identified to CDK2. This study allowed the understanding of the struc- ture of the complexes between CDK1/ CDK3 with inhibi- tors. The knowledge of their structural features mainly the biding sites might be useful to discovery and rationaliza- tion of drug design process. Keywords: Cyclin-dependent kinases · CDK1 · CDK3 · Molecular docking Mol. Inf. 2011, 30, 219 – 231  2011 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 219