Structure guided design of potential inhibitors of human calcium-calmodulin dependent protein kinase IV containing pyrimidine scaffold

Bioorganic & Medicinal Chemistry Letters
Huma NazMd Imtaiyaz Hassan

Abstract

Calmodulin dependent protein kinase IV (CAMKIV) belongs to the serine/threonine protein kinase family and considered as an encouraging target for the development of novel anticancer agents. The interaction and binding behavior of three designed inhibitors of human CAMKIV, containing pyrimidine scaffold, was monitored by in vitro fluorescence titration and molecular docking calculations under physiological condition. In silico docking studies were performed to screen several compounds containing pyrimidine scaffold against CAMKIV. Molecular docking calculation predicted the binding of these ligands in active-site cavity of the CAMKIV structure correlating such interactions with a probable inhibition mechanism. Finally, three active pyrimidine substituted compounds (molecules 1-3) have been successfully synthesized and characterized by (1)H and (13)C NMR. Molecule 3 is showing very high binding-affinity for the CAMKIV, with a binding constant of 2.2×10(8), M(-1) (±0.20). All three compounds are nontoxic to HEK293 cells up to 50 μM. The cell proliferation inhibition study showed that the molecule 3 has lowest IC50 value (46±1.08 μM). The theoretical and experimental observations are significantly correlated. This study reveals som...Continue Reading

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Citations

May 27, 2016·European Journal of Medicinal Chemistry·Jitendra KumarB Jayaram
Dec 23, 2017·Journal of Biomolecular Structure & Dynamics·Sunayana Begum SyedMd Imtaiyaz Hassan
Jan 7, 2020·Current Topics in Medicinal Chemistry·Ahmad Abu Turab NaqviMd Imtaiyaz Hassan
May 1, 2017·Archives of Pharmacal Research·Shahzaib AhamadMd Imtaiyaz Hassan
Jul 30, 2020·Oxidative Medicine and Cellular Longevity·Preeti GuptaMd Imtaiyaz Hassan
Mar 17, 2019·Cancers·Mohammed SikanderSubhash C Chauhan
May 21, 2020·International Journal of Molecular Sciences·Mohd YousufMd Imtaiyaz Hassan
Feb 10, 2019·Scientific Reports·Maria VouraMd Imtaiyaz Hassan

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