Elfiky Abdo A, Elshemey Wael M
1Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt.
2Biochemistry and Structural Biology, Center of Molecular Protein Science CMPS, Lund University, Lund, Sweden.
Med Chem Res. 2016;25(5):1005-1008. doi: 10.1007/s00044-016-1533-y. Epub 2016 Mar 4.
Quantitative structure-activity relationship (QSAR) parameters are good indicators for the reactivity of direct-acting antiviral drugs. Since molecular structure is related to molecular function, careful selection of molecular substitutions will result in more drugs that are potent. In this work, QSAR parameters are selected in order to compare the four drugs used as nucleotide inhibitors (NIs) for non-structural 5B (NS5B) RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV). These drugs are: ribavirin (widely used over the last 20 years), sofosbuvir (approved on December 2013 by FDA), and finally IDX-184 and R7128 (phase IIb of clinical trial drugs). The nucleotide analogues uracil (U), guanine (G), and cytosine (C) from which these drugs are fabricated are also compared to that group of drugs. QSAR parameters suggested that the drug IDX-184 is the best among all of the studied NIs. It also shows that NIs are always more reactive than their parent nucleotide.
The active site environment of 12 amino acids coordinated with IDX-184 through two Mg. The interaction with HCV subtypes 1a, 2b, and 3b is better than 4a subtype.
定量构效关系（QSAR）参数是直接作用抗病毒药物反应活性的良好指标。由于分子结构与分子功能相关，精心选择分子取代基将产生更多强效药物。在本研究中，选择QSAR参数以比较四种用作丙型肝炎病毒（HCV）非结构5B（NS5B）RNA依赖性RNA聚合酶（RdRp）核苷酸抑制剂（NIs）的药物。这些药物分别是：利巴韦林（在过去20年中广泛使用）、索非布韦（于2013年12月获美国食品药品监督管理局批准），以及最后一种IDX-184和R7128（处于临床试验药物的IIb期）。还将这些药物所衍生的核苷酸类似物尿嘧啶（U）、鸟嘌呤（G）和胞嘧啶（C）与该组药物进行了比较。QSAR参数表明，在所有研究的核苷酸抑制剂中，药物IDX-184是最佳的。研究还表明，核苷酸抑制剂的反应活性总是高于其母体核苷酸。
12个氨基酸的活性位点环境通过两个镁离子与IDX-184配位。与HCV 1a、2b和3b亚型的相互作用优于4a亚型。
