Molecular modelling in the design of anticancer drugs

Cell cycle progression is tightly controlled by the activity of cyclin-dependent kinases (CDKs). CDKs are inactive as monomers, and activation requires binding to cyclins, a diverse family of proteins whose levels oscillate during the cell cycle, and phosphorylation by CDK-activating kinase (CAK) on a specific threonine residue. The central role of CDKs in cell cycle regulation makes them a promising target for studying inhibitory molecules that can modify the degree of cell proliferation, the discovery of specific inhibitors of CDKs such as purine derivatives and polyhydroxylated flavones has opened the way to investigation and design of antimitotic compounds. More than 50 CDK2 inhibitors have now been described, some presents IC50 at nanomolar concentrations. The structures of CDK2 in complexes with several different inhibitors have been described using biocristallography and structural bioinformatics. These compounds inhibit CDKs by binding to the catalytic domain of the CDK molecule in place of ATP, which prevents transfer of a phosphate group to the substrate. It has been observed in several structures of CDK2 complexed with inhibitors the participation of a molecular fork, composed by a C=O group of Glu81 and the N-H and C=O group of Leu83, in intermolecular hydrogen bonds between CDK2 and the inhibitors. This molecular fork, composed of two hydrogen bond acceptors (C=O) and one hydrogen bond donor (N-H), allows a wide range of different molecules to dock on to the ATP binding pocket. All these inhibitors have pairs of hydrogen bond partners that show complementarity to the molecular fork on CDK2, most of them involving at least two hydrogen bonds with the molecular fork.

The relevant structural features that may guide the structure based-design of a new generation of CDK inhibitors will be discussed in this lecture.