Singh Baljinder, Vishwakarma Ram A, Bharate Sandip B
Medicinal Chemistry Division, Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India.
Curr Comput Aided Drug Des. 2013 Sep;9(3):350-9. doi: 10.2174/15734099113099990020.
Prodiginines are a family of linear and cyclic oligopyrrole red-pigmented compounds possessing antibacterial, anticancer and immunosuppressive activities and are produced by actinomycetes and other eubacteria. Recently, prodiginines have been reported to possess potent in vitro as well as in vivo antimalarial activity against chloroquine sensitive D6 and multi-drug resistant Dd2 strains of Plasmodium falciparum. In the present paper, a QSAR and pharmacophore modeling for a series of natural and synthetic prodiginines was performed to find out structural features which are crucial for antimalarial activity against these D6 and Dd2 Plasmodium strains. The study indicated that inertia moment 2 length, Kier Chi6 (path) index, kappa 3 index and Wiener topological index plays important role in antimalarial activity against D6 strain whereas descriptors inertia moment 2 length, ADME H-bond donors, VAMP polarization XX component and VAMP quadpole XZ component play important role in antimalarial activity against Dd2 strain. Furthermore, a five-point pharmacophore (ADHRR) model with one H-bond acceptor (A), one H-bond donor (D), one hydrophobic group (H) and two aromatic rings (R) as pharmacophore features was developed for D6 strain by PHASE module of Schrodinger suite. Similarly a six-point pharmacophore AADDRR was developed for Dd2 strain activity. All developed QSAR models showed good correlation coefficient (r² > 0.7), higher F value (F >20) and excellent predictive power (Q² > 0.6). Developed models will be highly useful for predicting antimalarial activity of new compounds and could help in designing better molecules with enhanced antimalarial activity. Furthermore, calculated ADME properties indicated drug-likeness of prodiginines.
灵菌红素是一类具有抗菌、抗癌和免疫抑制活性的线性和环状寡聚吡咯红色素化合物，由放线菌和其他真细菌产生。最近，据报道灵菌红素对恶性疟原虫的氯喹敏感株D6和多药耐药株Dd2具有强大的体外和体内抗疟活性。在本文中，对一系列天然和合成的灵菌红素进行了定量构效关系（QSAR）和药效团建模，以找出对这些D6和Dd2疟原虫菌株具有抗疟活性至关重要的结构特征。研究表明，惯性矩2长度、基尔分子连接性6（路径）指数、κ3指数和维纳拓扑指数在针对D6菌株的抗疟活性中起重要作用，而描述符惯性矩2长度、药物代谢动力学（ADME）氢键供体、可变分子极化率（VAMP）极化XX分量和VAMP四极矩XZ分量在针对Dd2菌株的抗疟活性中起重要作用。此外，通过薛定谔软件套件的PHASE模块为D6菌株开发了一个五点药效团（ADHRR）模型，其药效团特征包括一个氢键受体（A）、一个氢键供体（D）、一个疏水基团（H）和两个芳香环（R）。类似地，为Dd2菌株的活性开发了一个六点药效团AADDRR。所有开发的QSAR模型均显示出良好的相关系数（r²>0.7）、较高的F值（F>20）和出色的预测能力（Q²>0.6）。开发的模型对于预测新化合物的抗疟活性将非常有用，并有助于设计具有增强抗疟活性的更好分子。此外，计算得到的ADME性质表明灵菌红素具有类药性。
