In silico studies of diarylpyridine derivatives as novel HIV-1 NNRTIs using docking-based 3D-QSAR, molecular dynamics, and pharmacophore modeling approaches

Wan Youlan; Tian Yafeng; Wang Wenjie; Gu Shuangxi; Ju Xiulian; Liu Genyan

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In silico studies of diarylpyridine derivatives as novel HIV-1 NNRTIs using docking-based 3D-QSAR, molecular dynamics, and pharmacophore modeling approaches

机译：在二氧化胺研究中的二芳基吡啶衍生物作为新型HIV-1 NNRTIS使用基于对接的3D QSAR，分子动力学和药物模型方法

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A series of novel diarylpyridine derivatives has recently been identified as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), and most of them exhibited potent activities against HIV-1 strains, with EC50 values in the low nanomolar range. However, the three-dimensional quantitative structure-activity relationships (3D-QSARs) and pharmacophore characteristics of these compounds remain to be studied. In the present study, forty-two diarylpyridine derivatives were firstly docked into HIV-1 reverse transcriptase, and molecular dynamics (10 ns) simulations were further performed to validate the reliability of the docking results, which indicated that residues Lys101, Tyr181, Tyr188, Phe227, and Trp229 might play important roles in binding with these diarylpyridines. The U-shaped docking conformations of all compounds were then used to construct 3D-QSAR and pharmacophore models. The satisfactory statistical parameters of CoMFA (q(loo)(2) = 0.665, r(ncv)(2) = 0.989, r(pred)(2) = 0.962, etc.) and CoMSIA (q(loo)(2) = 0.727, r(ncv)(2) = 0.988, r(pred)(2) = 0.912, etc.) models demonstrated that both constructed models had excellent predictability, and their contour maps gave insights into the structural requirements of the diarylpyridines for the anti-HIV-1 activity. A docking-conformation-based pharmacophore model, containing three hydrophobic centers, three hydrogen-bond acceptors, and three hydrogen-bond donors, was also established. The observations in this study might provide important information for the rational design and development of novel HIV-1 NNRTIs.

机译：最近已经鉴定为HIV-1非核苷逆转录酶抑制剂（NNRTIS）的一系列新的二芳基吡啶衍生物，并且它们中的大多数具有针对HIV-1菌株的有效活性，EC50在低纳米摩尔范围内具有EC50值。然而，仍然研究这些化合物的三维定量结构 - 活性关系（3D-qsars）和药物团特性。在本研究中，首先将四十二个二芳基吡啶衍生物衍生物进入HIV-1逆转录酶，进一步进行分子动力学（10ns）模拟以验证对接结果的可靠性，这表明残留物Lys101，Tyr181，Tyr188， PHE227和TRP229可能在与这些二芳基赖氨酸结合时发挥重要作用。然后使用所有化合物的U形对接构象构建3D QSAR和药物模型。 COMFA（Q（LOO）（2）= 0.665，R（NCV）（2）= 0.989，R（PREG）（2）= 0.962等）和COMSIA（Q（LOO）（2）（2））的令人满意的统计参数= 0.727，R（NCV）（2）= 0.988，R（P7）= 0.912等）模型表明，两种构造的模型具有出色的可预测性，并且它们的轮廓图对二芳基吡啶的结构要求进行了洞察力抗HIV-1活性。还建立了含有三种疏水中心，三种氢粘合受体和三种氢键供体的对接构象的药物综合模型。本研究的观察可能提供新型HIV-1 NNRTIS的理性设计和开发的重要信息。

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《RSC Advances》 |2018年第71期|共15页
作者
Wan Youlan; Tian Yafeng; Wang Wenjie; Gu Shuangxi; Ju Xiulian; Liu Genyan;
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Sch Chem Engn &

Pharm Key Lab Green Chem Proc Minist Educ Wuhan Hubei 430205 Peoples R China;

Sch Chem Engn &

Pharm Key Lab Green Chem Proc Minist Educ Wuhan Hubei 430205 Peoples R China;

Sch Chem Engn &

Pharm Key Lab Green Chem Proc Minist Educ Wuhan Hubei 430205 Peoples R China;

Sch Chem Engn &

Pharm Key Lab Green Chem Proc Minist Educ Wuhan Hubei 430205 Peoples R China;

Sch Chem Engn &

Pharm Key Lab Green Chem Proc Minist Educ Wuhan Hubei 430205 Peoples R China;

Sch Chem Engn &

Pharm Key Lab Green Chem Proc Minist Educ Wuhan Hubei 430205 Peoples R China;

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1. In silico studies of diarylpyridine derivatives as novel HIV-1 NNRTIs using docking-based 3D-QSAR, molecular dynamics, and pharmacophore modeling approaches [J] . Wan Youlan, Tian Yafeng, Wang Wenjie, RSC Advances . 2018,第71期

机译：在二氧化胺研究中的二芳基吡啶衍生物作为新型HIV-1 NNRTIS使用基于对接的3D QSAR，分子动力学和药物模型方法
2. In silico studies of diarylpyridine derivatives as novel HIV-1 NNRTIs using docking-based 3D-QSAR, molecular dynamics, and pharmacophore modeling approaches [J] . Youlan Wan, Yafeng Tian, Wenjie Wang, RSC Advances . 2018,第71期

机译：使用基于对接的3D-QSAR，分子动力学和药效团建模方法对二芳基吡啶衍生物作为新型HIV-1 NNRTI进行计算机研究
3. In silico studies of diarylpyridine derivatives as novel HIV-1 NNRTIs using docking-based 3D-QSAR, molecular dynamics, and pharmacophore modeling approaches [J] . Youlan Wan, Yafeng Tian, Wenjie Wang, RSC Advances . 2018,第71期

机译：使用基于对接的3D-QSAR，分子动力学和药效团建模方法对二芳基吡啶衍生物作为新型HIV-1 NNRTI进行计算机研究
4. In silico ligand-based (LB) and docking-based (DB) 3D-QSAR study of potent Chk2 inhibitors [C] . F. A. Pasha, M. Muddassar, So Ha Lee, Frontiers in the Convergence of Bioscience and Information Technologies . 2007

机译：在基于硅配体的（LB）和基于对接的（DB）3D-QSAR研究的有效的CHK2抑制剂
5. I. Structure-based molecular modeling and synthesis of indole derivatives as non-phenolic analogues of mycophenolic acid. II. 3D-QSAR studies using CoMFA on homotropane and tropane derivatives as dopamine transporter and serotonin transporter ligands. [D] . El-Araby, Moustafa El-Sayed. 2001

机译：I.基于结构的分子模型和吲哚衍生物作为霉酚酸的非酚类似物的合成。二。 3D-QSAR研究使用CoMFA对高碘烷和托烷衍生物作为多巴胺转运蛋白和5-羟色胺转运蛋白配体的研究。
6. In silico identification of novel PKC βII inhibitors: ligand and receptor based pharmacophore modeling virtual screening and molecular dynamics study [O] . Baljinder K Grewal, ME Sobhia 2012

机译：在计算机上鉴定新型PKCβII抑制剂：基于配体和受体的药效团建模虚拟筛选和分子动力学研究
7. Pharmacophore modeling, in silico screening, molecular docking and molecular dynamics approaches for potential alpha-delta bungarotoxin-4 inhibitors discovery [O] . R Barani Kumar, M Xavier Suresh, B Shanmuga Priya 2015

机译：药效团模型，计算机筛选，分子对接和分子动力学方法，用于潜在的α-δ银环蛇毒素-4抑制剂发现

In silico studies of diarylpyridine derivatives as novel HIV-1 NNRTIs using docking-based 3D-QSAR, molecular dynamics, and pharmacophore modeling approaches

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