Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of drug-designing.
Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of drug-designing.
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DOI：
10.1371/journal.pone.0012029
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发表时间：
2010-08-16
期刊：
影响因子：
3.7
通讯作者：
Varma AK
中科院分区：
文献类型：
--
作者：
Patil R;Das S;Stanley A;Yadav L;Sudhakar A;Varma AK
在蛋白质结构的开放构象环境中，弱分子间相互作用（如氢键和疏水相互作用）是稳定能量有利配体的关键因素。然而，对于与这些相互作用相关的结合参数如何促进药物先导物识别特定靶标并提高药物功效，人们仍然知之甚少。为了理解这一点，我们对c-Src和c-Abl激酶与4-氨基取代1H-pyrazolo [3,4 -d]嘧啶化合物界面的疏水相互作用、氢键和结合亲和力进行了综合分析。利用Discovery Studio软件模块LigandFit、CDOCKER和ZDOCK进行了硅对接研究，以研究配体结合亲和力在c-Src和c-Abl激酶疏水口袋中的作用。用LigPlot程序比较了对接分子的疏水和氢键相互作用。此外，我们仔细检查了3D-QSAR和MFA计算，以量化弱相互作用在结合亲和力和药物功效中的作用。硅内方法使我们能够揭示多靶向小分子以低亲和力结合其各自的靶标。但是它的结合亲和力可以通过在配体-靶界面的活性位点整合构象有利的官能团来改变。对c-Src和c-Abl的生物活性级联上的4-氨基取代分子的对接研究表明，蛋白质-配体槽上的3D结构折叠也是多靶点化合物分子识别和预测其生物活性的标志。本文的研究结果表明，氢键和优化的疏水相互作用都能稳定靶位点的配体，并有助于改变结合亲和力和药物功效。
Weak intermolecular interactions such as hydrogen bonding and hydrophobic interactions are key players in stabilizing energetically-favored ligands, in an open conformational environment of protein structures. However, it is still poorly understood how the binding parameters associated with these interactions facilitate a drug-lead to recognize a specific target and improve drugs efficacy. To understand this, comprehensive analysis of hydrophobic interactions, hydrogen bonding and binding affinity have been analyzed at the interface of c-Src and c-Abl kinases and 4-amino substituted 1H-pyrazolo [3, 4-d] pyrimidine compounds. In-silico docking studies were performed, using Discovery Studio software modules LigandFit, CDOCKER and ZDOCK, to investigate the role of ligand binding affinity at the hydrophobic pocket of c-Src and c-Abl kinase. Hydrophobic and hydrogen bonding interactions of docked molecules were compared using LigPlot program. Furthermore, 3D-QSAR and MFA calculations were scrutinized to quantify the role of weak interactions in binding affinity and drug efficacy. The in-silico method has enabled us to reveal that a multi-targeted small molecule binds with low affinity to its respective targets. But its binding affinity can be altered by integrating the conformationally favored functional groups at the active site of the ligand-target interface. Docking studies of 4-amino-substituted molecules at the bioactive cascade of the c-Src and c-Abl have concluded that 3D structural folding at the protein-ligand groove is also a hallmark for molecular recognition of multi-targeted compounds and for predicting their biological activity. The results presented here demonstrate that hydrogen bonding and optimized hydrophobic interactions both stabilize the ligands at the target site, and help alter binding affinity and drug efficacy.
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