3D-QSAR and molecular docking studies on benzothiazole derivatives as Candida albicans N-myristoyltransferase inhibitors.
N-Myristoyltransferase has been a promising new target for the design of novel antifungal agents with new mode of action. Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, CoMFA and CoMSIA, were applied to a set of novel benzothiazole Candida albicans N-myristoyltransferase (CaNmt) inhibitors. The binding mode of the compounds at the active site of CaNmt was explored using flexible docking method and various hydrophobic and hydrogen-bonding interactions were observed between the benzothiazole inhibitors and the target enzyme. The best CoMFA and CoMSIA models had a cross-validated coefficient q(2) of 0.733 and 0.738, respectively, which showed high correlative and predictive abilities on both the test set and training set. The 3D contour maps of CoMFA and CoMSIA provided smooth and interpretable explanation of the structure-activity relationship for the compounds. The analysis of the 3D contour plots permitted interesting conclusions about the effects of different substituent groups at different position of the benzothiazole ring, which will guide the design of novel CaNmt inhibitors with higher activity.
Sheng
Chunquan
C
School of Pharmacy, Military Key Laboratory of Medicinal Chemistry, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
Zhu
Jie
J
Zhang
Wannian
W
Zhang
Min
M
Ji
Haitao
H
Song
Yunlong
Y
Xu
Hui
H
Yao
Jianzhong
J
Miao
Zhenyuan
Z
Zhou
Youjun
Y
Zhu
Jü
J
Lü
Jiaguo
J
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D052160:Benzothiazoles / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002176:Candida albicans / Q000201:enzymology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship
D052160:Benzothiazoles; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase