Montessori Siva Sivani Institute of Science and Technology-College of Pharmacy, Mylavaram, Vijayawada, 521 230, India.
BMC Complement Altern Med. 2013 Apr 15;13:85. doi: 10.1186/1472-6882-13-85.
Herpes viruses are important human pathogens that can cause mild to severe lifelong infections with high morbidity. They remain latent in the host cells and can cause recurrent infections that might prove fatal. These viruses are known to infect the host cells by causing the fusion of viral and host cell membrane proteins. Fusion is achieved with the help of conserved fusion machinery components, glycoproteins gB, heterodimer gH-gL complex along with other non-conserved components. Whereas, another important glycoprotein gD without which viral entry to the cell is not possible, acts as a co-activator for the gB-gH-gL complex formation. Thus, this complex formation interface is the most promising drug target for the development of novel anti-herpes drug candidates. In the present study, we propose a model for binding of gH-gL to gB glycoprotein leading from pre to post conformational changes during gB-gH-gL complex formation and reported the key residues involved in this binding activity along with possible binding site locations. To validate the drug targetability of our proposed binding site, we have repositioned some of the most promising in vitro, in vivo validated anti-herpes molecules onto the proposed binding site of gH-gL complex in a computational approach.
Hex 6.3 standalone software was used for protein-protein docking studies. Arguslab 4.0.1 and Accelrys® Discovery Studio 3.1 Visualizer softwares were used for semi-flexible docking studies and visualizing the interactions respectively. Protein receptors and ethno compounds were retrieved from Protein Data Bank (PDB) and Pubchem databases respectively. Lipinski's Filter, Osiris Property Explorer and Lazar online servers were used to check the pharmaceutical fidelity of the drug candidates.
Through protein-protein docking studies, it was identified that the amino acid residues VAL342, GLU347, SER349, TYR355, SER388, ASN395, HIS398 and ALA387 of gH-gL complex play an active role in its binding activity with gB. Semi flexible docking analysis of the most promising in vitro, in vivo validated anti-herpes molecules targeting the above mentioned key residues of gH-gL complex showed that all the analyzed ethno medicinal compounds have successfully docked into the proposed binding site of gH-gL glycoprotein with binding energy range between -10.4 to -6.4 K.cal./mol.
Successful repositioning of the analyzed compounds onto the proposed binding site confirms the drug targetability of gH-gL complex. Based on the free binding energy and pharmacological properties, we propose (3-chloro phenyl) methyl-3,4,5 trihydroxybenzoate as worth a small ethno medicinal lead molecule for further development as potent anti-herpes drug candidate targeting gB-gH-gL complex formation interface.
疱疹病毒是重要的人类病原体，可导致轻度至重度终生感染，发病率高。它们潜伏在宿主细胞中，并可引起可能致命的复发性感染。已知这些病毒通过引起病毒和宿主细胞膜蛋白的融合来感染宿主细胞。融合是在保守的融合机制成分、糖蛋白 gB、异二聚体 gH-gL 复合物以及其他非保守成分的帮助下实现的。另一方面，另一种重要的糖蛋白 gD 是病毒进入细胞所必需的，它作为 gB-gH-gL 复合物形成的辅助激活因子。因此，这个复合物形成界面是开发新型抗疱疹药物候选物的最有希望的药物靶点。在本研究中，我们提出了一个 gH-gL 与 gB 糖蛋白结合的模型，该模型导致 gB-gH-gL 复合物形成过程中的前构象到后构象变化，并报告了参与这种结合活性的关键残基以及可能的结合位点位置。为了验证我们提出的结合位点的药物靶位性，我们在计算方法中将一些最有前途的体外、体内验证的抗疱疹分子重新定位到 gH-gL 复合物的建议结合位点上。
使用 Hex 6.3 独立软件进行蛋白质-蛋白质对接研究。Arguslab 4.0.1 和 Accelrys®Discovery Studio 3.1 Visualizer 软件分别用于半柔性对接研究和相互作用的可视化。蛋白质受体和ethno 化合物分别从蛋白质数据库 (PDB) 和 Pubchem 数据库中检索。Lipinski's Filter、Osiris Property Explorer 和 Lazar 在线服务器用于检查候选药物的药物适宜性。
通过蛋白质-蛋白质对接研究，确定 gH-gL 复合物的氨基酸残基 VAL342、GLU347、SER349、TYR355、SER388、ASN395、HIS398 和 ALA387 在其与 gB 的结合活性中发挥积极作用。针对上述 gH-gL 复合物关键残基的最有前途的体外、体内验证的抗疱疹分子的半柔性对接分析表明，所有分析的民族药用化合物都已成功对接入 gH-gL 糖蛋白的建议结合位点，结合能范围在-10.4 到-6.4 K.cal/mol 之间。
成功地将分析化合物重新定位到建议的结合位点上，证实了 gH-gL 复合物的药物靶位性。基于游离结合能和药理学特性，我们建议（3-氯苯基）甲基-3,4,5 三羟基苯甲酸酯作为有前途的民族药用先导分子，进一步开发为针对 gB-gH-gL 复合物形成界面的有效抗疱疹药物候选物。
