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World J Pharmacol. Dec 9, 2014; 3(4): 162-173
Published online Dec 9, 2014. doi: 10.5497/wjp.v3.i4.162
Pharmacophore approaches in protein kinase inhibitors design
Sergiy A Starosyla, Galyna P Volynets, Volodymyr G Bdzhola, Andriy G Golub, Sergiy M Yarmoluk
Sergiy A Starosyla, Galyna P Volynets, Volodymyr G Bdzhola, Sergiy M Yarmoluk, Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, NAS of Ukraine, 03680 Kyiv, Ukraine
Andriy G Golub, OTAVA Ltd., 400 Applewood Crescent, Unit 100, Vaughan, Ontario L4K0C3, Canada
Author contributions: Starosyla SA and Volynets GP contributed equally to this work, generated the figures and wrote the manuscript; Bdzhola VG and Golub AG contributed to the writing of the manuscript; Yarmoluk SM designed the aim of the editorial and wrote the manuscript.
Correspondence to: Dr. Sergiy M Yarmoluk, Sci., Professor, Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo St., 03680 Kyiv, Ukraine. sergiy@yarmoluk.org.ua
Telephone: +38-44-5222458 Fax: +38-44-5222458
Received: June 27, 2014
Revised: October 15, 2014
Accepted: October 28, 2014
Published online: December 9, 2014
Abstract

Protein kinases constitute a superfamily of therapeutic targets for a number of human and animal diseases that include more than 500 members accordingly to sequencing data of the human genome. The well characterized nature of protein kinases makes them excellent targets for drug development. Pharmacophore approaches have become one of the major tools in the area of drug discovery. Application of pharmacophore modeling approaches allows reducing of expensive overall cost associated with drug development project. Pharmacophore models are important functional groups of atoms in the proper spatial position for interaction with target protein. Various ligand-based and structure-based methods have been developed for pharmacophore model generation. Despite the successes in pharmacophore models generation these approaches have not reached their full capacity in application for drug discovery. In the following review, we summarize the published data on pharmacophore models for inhibitors of tyrosine protein kinases (EGFR, HER2, VEGFR, JAK2, JAK3, Syk, ZAP-70, Tie2) and inhibitors of serine/threonine kinases (Clk, Dyrk, Chk1, IKK2, CDK1, CDK2, PLK, JNK3, GSK3, mTOR, p38 MAPK, PKB). Here, we have described the achievements of pharmacophore modeling for protein kinase inhibitors, which provide key points for further application of generated pharmacophore hypotheses in virtual screening, de novo design and lead optimization.

Keywords: Protein kinase, Inhibitor, Pharmacophore model, Receptor-based method, Ligand-based method

Core tip: In the following review, we summarize the published data on pharmacophore models for inhibitors of tyrosine protein kinases (EGFR, HER2, VEGFR, JAK2, JAK3, Syk, ZAP-70, Tie2) and inhibitors of serine/threonine kinases (Clk, Dyrk, Chk1, IKK2, CDK1, CDK2, PLK, JNK3, GSK3, mTOR, p38 MAPK, PKB). Here, we have described the achievements of pharmacophore modeling for protein kinase inhibitors, which provide key points for further application of generated pharmacophore hypotheses in virtual screening, de novo design and lead optimization.