Probing the ATP Ribose-Binding Domain of Cyclin-Dependent Kinases 1 and 2 withO⁶-Substituted Guanine Derivatives

Abstract

O(6)-substituted guanines are adenosine 5'-triphosphate (ATP) competitive inhibitors of CDK1/cyclin B1 and CDK2/cyclin A, the O(6) substituent occupying the kinase ribose binding site. Fifty-eight O(6)-substituted guanines were prepared to probe the ribose pocket, and the structures of four representative compounds bound to monomeric CDK2 were determined by X-ray crystallography. Optimum binding occurs with a moderately sized aliphatic O(6) substituent that packs tightly against the hydrophobic patch presented by the glycine loop, centered on Val18, an interaction promoted by the conformational restraints imposed in a cyclohexylmethyl or cyclohexenylmethyl ring. Structure-based design generated (R)-(2-amino-9H-purin-6-yloxymethyl)pyrrolidin-2-one (56), which reproduces the reported hydrogen bonds formed between ATP and Asp86 and Gln131 but failed to improve inhibitory potency. Thus, the parent compound O(6)-cyclohexylmethylguanine (NU2058, 25) is the preferred starting point for exploring other areas of the kinase active site.

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

“…These provide a clear picture of the binding features between the ligand and those residues that constitute the binding pocket, revealing the dominant interactions to be hydrogen bonding, electrostatic and van der Waals forces. 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.…”

Molecular Basis for Nucleotide-binding Specificity: Role of the Exocyclic Amino Group “N2” in Recognition by a Guanylyl-ribonuclease

“…As such, a number of potential drug targets are nucleotide-binding proteins. [2][3][4][5][6][7][8][9][10][11] The high conservation of nucleotide-binding sites [12][13][14][15][16][17][18][19] makes the design of drugs with adequate specificity for a particular nucleotide-binding protein difficult. Dissection of the protein-nucleotide interaction on the molecular level by comparing the binding of closely related nucleotides will begin to identify the key determinants of specificity that can be incorporated into structurebased drug design efforts.…”

Fragment-Based de Novo Ligand Design by Multiobjective Evolutionary Optimization

“…The distribution of the calculated binding energy versus the molecular weight reveals that most of the molecules designed by GANDI are located between two series of known inhibitors with micromolar 53 by GANDI revealed that 32% of the former show a distinct binding mode (RMSD > 2 Å) with more favorable free energy of binding than the latter. Furthermore, only 9% of the redocked molecules have a ∆G bind LIECE more favorable by more than 1 kcal mol -1 than the GANDI pose.…”