Current Enzyme Inhibition (v.13, #2)

Meet Our Co-Editor by Dimitra Hadjipavlou-Litina (79-79).

Overview of the Structure and Function of Protein Kinases by Sugunadevi Sakkiah, Guang Ping Cao, Staya P. Gupta, Keun Woo Lee (81-88).
After G protein-coupled (GPC) receptors, protein kinases are considered as most important drug targets. Kinase family consists of multigene, which is particularly relevant to various diseases. Protein phosphorylation by kinases plays a crucial activity in many cellular processes like apoptosis, cell division, survival, metabolism, etc. The emergence of various protein kinases crystal structures from many research groups gives a deep insight to understand the catalysis and regulation of different protein kinases. This review will mainly focus on the active site structures and functions of few kinases related to different families such as Protein A, G, and C kinase family (AGC), Ca2+/Calmodulin-dependent kinase family (CaMK), Cyclin-dependent kinase family (CMGC), Receptor guanylatecyclase family (RGC), Tyrosine kinase family (TK), Tyrosine kinase-like family (TKL), Sterile 20 Serine/threonine kinase family (STE), and Casein kinase 1 family (CK1).

Specificity of Binding in Protein Kinases by Satya P. Gupta, Basheerulla Shaik, Vijay K. Agrawal (89-98).
Objective: To delineate specificity of binding in protein kinases with its substrate or inhibitors so that the design of its inhibitors can be facilitated.

Background: For the treatment of a variety of disorders in humans such as cancer, inflammation, diabetes, infections, cardiovascular diseases, etc., protein kinases have been found as a very prominent target and thus attempts have been made to find the potent inhibitors of these kinases. The knowledge of specificity of binding of any enzyme with its substrate or inhibitors greatly facilitates the design of its inhibitors. In this article, thus, attempt has been made to highlight the specific features of kinases that are important for them to bind with the substrates or inhibitors.

Method: It is a review article so attempt has been made to compile all the theoretical and experimental studies on specificity of binding in protein kinases and critically analyze them in the light of drugs designed based on such knowledge.

Results: From various studies, it has been suggested that all protein kinases have a similar protein fold comprised of two lobes, where one lobe is a small N-lobe made of β -sheets and the other one is a larger C-lobe consisting of α -helices. This protein fold forms an ATP binding cleft that constitutes the active site of the enzyme. Further, the specific features of active site of kinases, that have been found to be usually responsible for its binding preference for the substrate or inhibitors, are its depth, charge, and hydrophobic nature.

Conclusion: It has been pictured out that in all protein kinases, the catalytic domain has a hinge region, a hydrophobic channel, a hydrophobic back-pocket and a sugar pocket, which can easily accommodate a substrate or an inhibitor that may complement these features. Protein kinases have also been found to achieve substrate specificity through localization to distinct subcellular compartments or structures. Selectivity of inhibitors also depends on potency. In protein kinases, there is a strong correlation between inhibitor potency and selectivity.

Application: This knowledge can be greatly exploited to design and develop potent kinase inhibitors for the treatment of a variety of disorders in humans such as cancer, inflammation, diabetes, infections, cardiovascular diseases, etc.


Protein Kinases as Drug Targets in Human and Animal Diseases by Suvarna G. Kini, Vikas Garg, Sharada Prasanna, Revathi Rajappan, Muhammad Mubeen (99-106).
Almost thirty percent of the protein targets currently under exploration and study constitute the protein kinases which have always attracted the pharmaceutical companies as they are easy targets for drug development. Although the kinases will remain major focus of oncology for many years to come in the development of anticancer drugs, the number of kinase inhibitors as therapeutic targets for the treatment of several other diseases which are undergoing clinical trials are exponentially increasing. In this review, we discuss very briefly the different types of protein kinases that have been used as targets for developing drugs for cancer, inflammation, autoimmune disease, heart disease and animal diseases.

The current review deals with the involvement of glycogen synthase kinase-3 (GSK-3) in major neurodegenerative disorders like Alzheimer's Disease (AD), Cerebral ischemia, Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS). GSK-3 is a proline-directed serine/threonine kinase, considered as a key influencer in these pathologies. From gene to protein, every process has crucial involvement in the genesis of disease. Gene splicing of exon 8 and 9 is more distinct in the function compared to the native one. GSK-3 mRNA and protein are involved in transcribing a variety of genes that are involved in the progression of pathology. Post-translational modification of GSK-3 by multiple substrates further regulates downstream messengers and their response in multiple pathologies. This conserved functioning of GSK-3 makes it a viable target. Various competitive and non-competitive GSK-3 inhibitors slowed the progression and modified onset of disease. Inhibition of GSK-3 alters the neurobiology of disease, thereby having a beneficial effect. However, none of these inhibitors, till date found promising efficacy in reversing the state of pathology, raising questions about the mode and magnitude of inhibition. Involvement of GSK-3 in multiple signaling cascades can pull down inhibition efficacy in pathology. Efforts are needed to generate inhibitors which can block both the prime and ATP binding site or a small hydrophobic pocket defined by Ile62, Gly63, and Phe67 residues. These types of inhibitors may have better effects compared to existing ones. Inhibiting multiple targets respective to the disease concerned, along with GSK-3 inhibition may have more therapeutic benefits than inhibiting alone GSK-3 alone.

The Polyhedric Abl Kinases and their Pharmacologic Inhibitors by Elisa Lupino, Marco Piccinini (129-138).
The Abl family of non-receptor tyrosine kinases encoded by the genes ABL1 and ABL2 are part of the signaling pathways that control cell proliferation, migration and apoptosis. The activity of Abl family kinases is tightly controlled through an autoinhibitory mechanism based on intramolecular interactions controlling the activity of the kinase domain. Activation of Abl kinases is promoted by phosphorylation by upstream kinases or engagement by interaction partners and results in a conformational modification of the kinase domain. Abl kinases are frequently deregulated in human leukemias because of chromosomal abnormalities that lead to the expression of fusion proteins such as BCRAbl1. No activating Abl mutations have been detected in solid tumors, however in many of them, increased c-Abl/Arg activity has been revealed. The reported capacity of c-Abl to promote the downregulation of the CDK inhibitors p27KIP1 and p21CIP1 in hematological as well as in solid tumors offers an explanation for the mechanism of the mitogenic effect of Abl activation.

Objective: To investigate the various physicochemical descriptors employed towards biological activity of tyrosine kinase inhibitors.

Background: In oncology, kinase domain has emerged as an important pharmacological target. The receptor tyrosine kinases on deregulation (i.e. over expression, chromosomal translocation, gene amplication, mutation) contribute towards development of cancer and thus it has been emerged as potential target in oncology.

Method: The available 2D/3D-QSAR methodologies like Hansch analysis, CoMFA, CoMSIA provide the models to correlate biological activity with their 2D/3D descriptors. The identified electrostatic, steric, H-bond, hydrophobic interaction energies involved in ligand-receptor interactions were analyzed.

Results: The QSAR models derived for some of the well reported and evaluated tyrosine kinase inhibitors like benzimidazole, pyrido[2,3-d]pyrimidine, quniazolines, quinolines, pyrrolo-pyrimidines, biphenyl amide-based, phenylaminopyrimidine-based, indolinones, and 1,4-dihydroindeno[1,2-c]pyrazole derivatives have found to be useful to investigate the mechanism of tyrosine kinase inhibition.

Conclusion: The validated and tested QSAR and 3D-QSAR models for different chemical classes of tyrosine kinase inhibitors have acceptable predictive power.

Application: The compiled data on some of the available derived 2D/3D-QSAR models as well as contributing descriptors has utility in understanding structure-activity relationship studies in respect to various endpoints within the chemical series.