Pharmacophore identification and validation study of CK2 inhibitors using CoMFA/CoMSIA.
Protein kinase CK2, also known as casein kinase-2, has been found to be involved in cell growth, proliferation and suppression of apoptosis, which is related to human cancers. The series of compounds were identified as casein kinase-2 inhibitors and their inhibitory activities are a function of a variation of their structures. The current study deals with the pharmacophore identification and, accordingly, the three-dimensional quantitative structure-activity relationship model development using Pharmacophore Alignment and Scoring Engine. Several hypotheses were developed for the molecular alignments. On the basis of statistical values, the best-fitted model was identified and the same alignment was used for 3D-QSAR using comparative molecular field analysis/comparative molecular similarity index analysis. Both the CoMFA (R(2)(CV) = 0.58, R(2) = 0.82 and r(2)(pred) = 0.62) and the comparative molecular similarity index analysis (R(2)(CV) = 0.74, R(2) = 0.98 and r(2)(pred) = 0.81) gave reasonable results. Besides pharmacophore-based alignment, the maximum common substructure-based alignment was also used for the comparative molecular field analysis and comparative molecular similarity index analysis. The pharmacophore-based alignment was more prominent and it has provided important information for the modelling of potent inhibitors. The overall study implies that a highly positive and bulky group with H-bond donating property is desirable around the nitrogen atom adjacent to the pyrrolidine ring.
Morshed
Mohammad Neaz
MN
Korea Institute of Science and Technology, Seoul, South Korea.
Muddassar
Muhammad
M
Pasha
Farhan Ahmad
FA
Cho
Seung Joo
SJ
D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D016018:Least-Squares Analysis; D008956:Models, Chemical; D008968:Molecular Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D014227:Triazines; D047390:Casein Kinase II