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  • The cyclin dependent kinase deactivation

    2019-08-28

    The cyclin-dependent kinase deactivation is carried out by a particular group of proteins cyclin-dependent kinase inhibitors (CDKIs). These group of proteins blocks kinase activity by interfering with the interaction of cyclin-CDK complex [43]. The inhibition of CDK naturally occurs during a G1 phase in response to signals from damaged DNA. In the eukaryotic cells, there are two types of naturally occurring (CDKIs) families namely the INK4 (inhibitor of CDK4/6) family and the CIP/KIP (inhibit other CDKs) [44]. The INK4 family comprises of p16INK4a, p18INK4c, p15INK4b, and p19INK4 which are specific inhibitors of CDK4 and CDK6, that binds to the CDK monomers [45]. These proteins are also reported to play a major role in tumor suppression, aging, apoptosis and DNA repair [46]. CIP/KIP proteins are nonspecific and bind to biotin 100 mg and CDK or cyclin/CDK complex. This family of proteins enhances complex cyclin D-CDK4/6 formation by activation of cyclin D [43]. The dysregulated activation of CDKs has been associated with various cancers, viral infections [47], [48], Alzheimer [49], Parkinson [50], [51], renal diseases [52] and ischemia [47], [48]. The role of CDKs in the pathogenesis of various diseases has encouraged an intensive search for potent and selective pharmacological inhibitors of CDKs [53]. The inhibition of the CDKs occurs naturally by INK4s and CIPs. Small molecules are being discovered and developed as CDK inhibitors which mainly target ATP binding domain of CDK-cyclin complexes in a reversible and competitive manner or by allosteric inhibition (Fig. 3) [54], [55]. Betzi et al. elucidated the structure of CDK2 with the inhibitor ANS that acts on allosteric site [56], [57]. In 2015, palbocicilib was approved by FDA as CDK4/6 inhibitor. Recently, ribocicilib (Kisqali) and abemacicilib are approved by FDA in March and July 2017, respectively. Although several CDK inhibitors such as, selicicilib, micicilib, dinacicilib, AT7519, atuvecicilib, SNS-032, etc. are in various clinical phases and some (covalent inhibitors: THZ1, THZ531, and BS-181, LDC000067) are under preclinical development stage (Fig. S3) but developing a potent and selective inhibitor is still a challenge (Fig. 4) [58], [59], [60], [61]. A review by Roskoski covered CDK inhibitors in clinical and preclinical studies [54]. Recently Li et al. published a review article which mainly dealt with CDK inhibitors and their structure-activity relationship studies [55]. The present manuscript is first of its kind, its first part highlights on overview of each class of CDKs, their inhibitors, and their available X-ray crystal structures till date. The next section deals with factors contributing to the selective inhibition of a particular CDK based on either active site residues of CDK, ligand-CDK binding or chemical architecture of ligand, etc. The facts were further corroborated by taking case studies and performing computational studies.
    CDKs: Location, X-ray structures, and sequence alignment
    Specificity of the CDKs: The structural insights leading to design of specific inhibitors The criteria affecting the ligand-receptor interaction and specificity are:-
    Conclusion Among all the essential proteins involved in cell division, cyclin-dependent kinases are the most imperative. CDKs comprise of the multifunctional enzymes that can transform various protein substrates associated with the cell cycle progression. CDKs are found to be extensively involved in cancer both directly and through crosstalk(s) cascades including mitogenic and non-mitogenic dependent pathways. Till date, few CDK inhibitors are discovered, but they lack specificity hence commonly abbreviated as Pan Inhibitors. In this league, the revolutionary introduction of CDK 4/6 inhibitor palbociclib has led to the idea of specific inhibitors of CDKs. After the palbociclib approval, other drugs abemacicilib and ribociclib were introduced, and in the current year these were approved as CDK4/6 inhibitors. However, the design of the specific CDK inhibitor has remained a challenge till date. In the present work, we have put forth the idea of the selective design of potent and specific CDK inhibitor. The approach involved a comparative analysis of structural differences between several CDKs ATP binding site and their inhibitor specificity by depicting the principal ligand- CDK interactions for individual CDKs (Fig. 23) to be targeted. The important find outs for CDK specific inhibitor design can be created by taking into consideration the amino acid residues changes, nature of amino acid(s) in the active site of CDK, conformational changes of the residues in active site, interacting residues, binding energy, and the properties like volume of ligand, volume of active site, remote cysteine residue for covalent inhibition, etc. These parameters have been briefly explained by taking an example in each case. Therefore, it is expected that the current findings would provide ample scope and opportunities to the medicinal and computational researchers to discover and design novel and selective CDK inhibitors as therapeutic strategies to treat various types of cancer.