Homology Model of the CDK1/cyclin B Complex

Abstract

We describe a refined homology model of a CDK1/cyclin B complex that was previously used for the structure-based optimization of the Paullone class of inhibitors. The preliminary model was formed from the homologous regions of the deposited CDK2/cyclin A crystal structure. Further refinement of the CDK1/cyclin B complex was accomplished using molecular mechanics and hydropathic analysis with a protocol of constraints and local geometry searches. For the most part, our CKD1/cyclin B homology model is very similar to the high resolution CDK2/cyclin A crystal structure regarding secondary and tertiary features. However, minor discrepancies between the two kinase structures suggest the possibility that ligand design may be specifically tuned for either CDK1 or CDK2. Our examination of the CDK1/cyclin B model includes a comparison with the CDK2/cyclin A crystal structure in the PSTAIRE interface region, connecting portions to the ATP binding domain, as well as the ATP binding site itself.

N‐(Indazolyl)benzamido Derivatives as CDK1 Inhibitors: Design, Synthesis, Biological Activity, and Molecular Docking Studies

“…In particular, they present only two differences at positions 84 and 85 in their amino acidic composition which can be considered as minor difference, since their chains project outside the ATP-binding pocket and are not involved in ligand binding [20]. Furthermore, the hydrogen bond nucleoside recognition site remains relatively unchanged in the CDK1 model compared with the CDK2 crystal structure with a RMS (root mean square) deviation of the backbone on these residues of 0.23 [19]. Finally, the molecular fork identified in CDK2 structures seems to be conserved in the CDK1 structure suggesting that CDK1 may also be strongly inhibited by CDK2 inhibitors [21].…”

“…The crystallographic structure of CDK1 has not yet been determined, there is report of homology modelling of CDK1 [19]. The comparison between the sequences of the CDK1 and CDK2 proteins shows that these two proteins share 66% of identity with a similarity of 84%.…”

The anticancer potential of various substituted pyridazines and related compounds

“…2004). We now became interested in the synthesis of the new molecule, 1,5-dimethyl-6H-pyridazino [4,5-b]carbazole derivatives, as a 3-aza isoster of olivacine, which was required as a reference compound (Sims, et al, 2003;McGrath, et al, 2005;Teague. 2003).…”

“…These agents are represented by the substituted thieno [3,2-b]pyrrole [3, 2-d] pyridazinone 46 and substituted N,N′-diaryl sulfonamide 47. The report detailing NCGC00030335 (47), it was essential to establish the cooperative nature of these agents with the native substrates of PKM2. Given the allosteric activation of PKM2 by FBP, it was desirable to examine how our lead chemotypes affected the steady-state kinetics of PEP and ADP.…”

3-Chloro-4-(5-methoxy-1H-indol-3-yl)cyclobut-3-ene-1,2-dione

“…With the aim to develop protein kinase inhibitors based on novel scaffolds by structure-guided design methods [5] we were interested to combine the indole ring system with squaric acid derived structure elements. The latter have recently been highlighted as "unusual" chemical structures with high potential for drug development [6].…”