Loop Flexibility and Solvent Dynamics as Determinants for the Selective Inhibition of Cyclin‐Dependent Kinase 4: Comparative Molecular Dynamics Simulation Studies of CDK2 and CDK4

Abstract

The design and discovery of selective cyclin-dependent kinase 4 (CDK4) inhibitors have been actively pursued in order to develop therapeutic cancer treatments. By means of a consecutive computational protocol involving homology modeling, docking experiments, and molecular dynamics simulations, we examine the characteristic structural and dynamic properties that distinguish CDK4 from CDK2 in its complexation with selective inhibitors. The results for all three CDK4-selective inhibitors under investigation show that the large-amplitude motion of a disordered loop of CDK4 is damped out in the presence of the inhibitors whereas their binding in the CDK2 active site has little effect on the loop flexibility. It is also found that the binding preference of CDK4- selective inhibitors for CDK4 over CDK2 stems from the reduced solvent accessibility in the active site of the former due to the formation of a stable hydrogen-bond triad by the Asp99, Arg101, and Thr102 side chains at the top of the active-site gorge. Besides the differences in loop flexibility and solvent accessibility, the dynamic stabilities of the hydrogen bonds between the inhibitors and the side chain of the lysine residue at the bottom of the active site also correlate well with the relative binding affinities of the inhibitors for the two CDKs. These results highlight the usefulness of this computational approach in evaluating the selectivity of a CDK inhibitor, and demonstrate the necessity of considering protein flexibility and solvent effects in designing new selective CDK4-selective inhibitors.

Molecular dynamics simulations on the inhibition of Cyclin-Dependent Kinases 2 and 5 in the presence of activators

“…However, simulations using monomeric CDK2 and CDK4 complexes with NU6102 like inhibitors [25] have predicted that the distance between the Thr14 in CDK2 (Ala16 in CDK4) and the Gly147 and the distance between the Ala16 in CDK4 and the Gly160 decrease slightly when the inhibitors bind to the kinases. Different results have also been obtained when the activators are included in the simulations.…”

“…In the past decade, several theoretical studies on CDKs based on both molecular dynamic simulations and quantum mechanical calculations [20][21][22][23][24][25][26][27][28][29] have been carried out to supplement the abundance of experimental works. However, most simulations are based solely on monomeric CDK templates and do not take into account the activators.…”

Combining docking and molecular dynamic simulations in drug design

“…Park et al 109 studied the differential inhibition of two cyclin-dependent kinases (CDKs), CDK2, and CDK4, by three different selective inhibitors. The final MD simulations of the docked complexes provided molecular insight into the preferential binding of the inhibitors to CDK4.…”

Why pyridine containing pyrido[2,3-d]pyrimidin-7-ones selectively inhibit CDK4 than CDK2: Insights from molecular dynamics simulation

“…Few groups have employed computational models to successfully design CDK4 specific inhibitors [9][10][11]. Few theoretical studies have also been undertaken to elucidate the selective mechanism of CDK4 inhibition [12][13][14]. The biochemical evaluation of pyrazolopyrimidinones identified hydrogen bonding interactions to a couple of hinge residues, namely His95 and Lys22 in CDK4, to be largely responsible for the observed selectivity [11].…”