Pal Ria, Islam Md Ataul, Hossain Tabassum, Saha Achintya
Department of Chemical Technology, University of Calcutta, 92, A.P.C. Road, Kolkata-700009, India.
Sci Pharm. 2011 Jul-Sep;79(3):461-77. doi: 10.3797/scipharm.1105-03. Epub 2011 Jun 30.
Considering the significance of progesterone receptor (PR) modulators, the present study is explored to envisage the biophoric signals for binding to selective PR subtype-A using ligand-based quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies on nonsteroidal substituted quinoline and cyclocymopol monomethyl ether derivatives. Consensus QSAR models (Training set (Tr): n(Tr)=100, R(2) (pred)=0.702; test set (Ts): n(Ts)=30, R(2) (pred)=0.705, R(2) (m)=0.635; validation set (Vs): n(Vs)=40, R(2) (pred)=0.715, R(2) (m)=0.680) suggest that molecular topology, atomic polarizability and electronegativity, atomic mass and van der Waals volume of the ligands have influence on the presence of functional atoms (F, Cl, N and O) and consequently contribute significant relations on ligand binding affinity. Receptor independent space modeling study (Tr: n(Tr)=26, Q(2)=0.927; Ts: n(Ts)=60, R(2) (pred)=0.613, R(2) (m)=0.545; Vs: n(Vs)=84, R(2) (pred)=0.611, R(2) (m)=0.507) indicates the importance of aromatic ring, hydrogen bond donor, molecular hydrophobicity and steric influence for receptor binding. The structure-function characterization is adjudged with the receptor-based docking study, explaining the significance of the mapped molecular attributes for ligand-receptor interaction in the catalytic cleft of PR-A.
鉴于孕激素受体（PR）调节剂的重要性，本研究旨在通过基于配体的定量构效关系（QSAR）和药效团空间建模研究，设想非甾体取代喹啉和环 cymopol 单甲醚衍生物与选择性 PR 亚型-A 结合的生物活性信号。共识 QSAR 模型（训练集（Tr）：n(Tr)=100，R(2)（预测）=0.702；测试集（Ts）：n(Ts)=30，R(2)（预测）=0.705，R(2)（平均）=0.635；验证集（Vs）：n(Vs)=40，R(2)（预测）=0.715，R(2)（平均）=0.680）表明，配体的分子拓扑结构、原子极化率和电负性、原子质量和范德华体积对官能团原子（F、Cl、N 和 O）的存在有影响，从而对配体结合亲和力有显著影响。受体独立空间建模研究（Tr：n(Tr)=26，Q(2)=0.927；Ts：n(Ts)=60，R(2)（预测）=0.613，R(2)（平均）=0.545；Vs：n(Vs)=84，R(2)（预测）=0.611，R(2)（平均）=0.507）表明，芳香环、氢键供体、分子疏水性和空间影响对受体结合很重要。通过基于受体的对接研究对结构-功能特征进行了判定，解释了 PR-A 催化裂隙中映射的分子属性对配体-受体相互作用的重要性。
