Pharmacophore-based 3D-QSAR of HIF-1 inhibitors.
(Aryloxyamino)benzoic acids and nicotinic/isonicotinic acids represent an important new class of small molecules that inhibit the activation of hypoxia-inducible factor (HIF)-1. In order to understand the factors affecting inhibitory potency of HIF-1 inhibitors, 3 dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed. Since no receptor structure are available, the pharmacophore-based alignment was used for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA and CoMSIA models gave reasonable statistics (CoMFA: q(2) = 0.564, r(2)=0.945; CoMSIA: q(2) = 0.575, r(2)=0.929). Both CoMFA and CoMSIA results indicate that the steric interaction is a major factor, while CoMSIA suggests importance of hydrogen bonding. These findings about steric and H-bonding effects can be useful to design new inhibitors.
Chung
Jae Yoon
JY
Korea Institute of Science and Technology, Seoul, 130-650, Korea.
Pasha
F A
FA
Cho
Seung Joo
SJ
Won
Misun
M
Lee
Jung Joon
JJ
Lee
Kyeong
K
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry; D017076:Computer-Aided Design; D015195:Drug Design; D006860:Hydrogen Bonding; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D021621:Imaging, Three-Dimensional; D007539:Isonicotinic Acids / Q000737:chemistry; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000737:chemistry; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results
D000970:Antineoplastic Agents; D001565:Benzoates; D051793:Hypoxia-Inducible Factor 1; D007539:Isonicotinic Acids; D008024:Ligands; D009539:Nicotinic Acids