3D-QSAR CoMFA on Cyclin-Dependent Kinase Inhibitors

Abstract

Several series of cyclin-dependent kinase inhibitors previously prepared in our laboratory were compared using 3D-QSAR (CDK1) and docking (CDK2) techniques. Evaluation of our own library of 93 purine derivatives served to establish the model which was validated by evaluation of an external library of 71 compounds. The best predictions were obtained with the CoMFA standard model (q(2) = 0.68, r(2) = 0.90) and with the CoMSIA combined steric, electrostatic, and lipophilic fields (q(2) = 0.74, r(2) = 0.90). The CDK1 3D-QSAR model was then superimposed to the ATP/CDK2 binding site, giving direct contour maps of the different fields. Although too few compounds were evaluated on CDK5 to derive a 3D-QSAR model, some interesting SARs have been deduced. Comparison of the results obtained from both methods helped with understanding the specific activity of some compounds and designing new specific CDK inhibitors.

Novel Structural Features of CDK Inhibition Revealed by an ab Initio Computational Method Combined with Dynamic Simulations

“…Potent lead compounds for new CDK inhibitors have been readily developed by taking advantage of these interactions via analysis of the so-called structure-activity relationship [12,[15][16][17][18]. In addition, computeraided approaches such as database [19], docking [20][21][22] and scoring function methods [23] provide an effective way of probing the binding modes and testing the binding strength of large arrays of molecules, and thus help identify potential new lead compounds. Moreover, molecular dynamics simulations have proven very useful for analysis of the binding modes and the structural rearrangements which are connected with the inhibition or activation of CDKs [24][25][26][27].…”

Targeting the cell cycle and the PI3K pathway: A possible universal strategy to reactivate innate tumor suppressor programmes in cancer cells

“…The 2,6,9-trisubstituted purines used in this study differ from each other, and from roscovitine, by the presence of either a pyrrolidine methanol or a 3-methylpent-1-yn-3-ol side chain at C-2, and by the nature of the substituents on the C-6 benzylamino/anilino groups (15)(16)(17). A systematic screen of a library of 130 compounds was made to compare their relative cytotoxicity toward ten cell lines differing in the Rb/p53 status, their tissue origin and their tumorigenic potential.…”

“…In the grey box is shown the structure of roscovitine (Ro); in pink boxes are shown structures of 6-benzyl-2-pyrrolidine methanol derivatives (1, 2, 3, 4, 5, 18, 19, 20, 21 and 22); in amber boxes, structures of 6-benzyl-2-alkynyl derivatives (11, 12, 13 and 23); in yellow boxes, structures of 6-benzyl-2-alkynyl derivatives (6, 7, 8, 9, 10 and 24); in green boxes, structures of 6-phenyl-2-alkynyl derivatives (14,15,16,17,25,26,27 …”

“…Preparation of the other 2,6,9-trisubstituted purine derivatives studied has been described elsewhere (15)(16)(17).…”

“…The cytotoxicity enhancement, however, varied depending on both the mode of cotreatment and the tumor cell type. The investigation was extended to a series of purine-based compounds differing from each other and from roscovitine by the nature of the C-2 and C-6 substituents (15)(16)(17). We showed that purines differing by a single substitution, which exerted little lethal effect on distant cell types in rich medium, could display widely-differing cytotoxicity profiles toward the same cell types in poor medium.…”