VEGFR-2 与抑制剂Sunitinib 的分子对接及分子动力学研究

用分子对接方法研究了VEGFR-2 和抑制剂Sunitinib 的相互作用模式, 并对其复合物进行了10 ns 的分子动力学(Molecular Dynamics, MD)模拟. 结果表明, 抑制剂Sunitinib 能与VEGFR-2 中位于活性空腔的Glu885, Ile888, His1026,Asp1028, Asp1046 五个氨基酸残基形成疏水作用; 另外, VEGFR-2 中His1026, Cys1024, Asp1046 三个氨基酸残基能与Sunitinib 形成三个作用强度不同的氢键. 这些基团之间的相互作用是Sunitinib 抑制VEGFR-2 活性的关键因素. 研究结果可为VEGFR-2 抑制剂的结构改良、分子设计、合成提供理论参考, 并有助于寻找活性更高、效果更好的抗肿瘤药物.     

DCN1-UBE2M相互作用抑制剂的3D-QSAR、分子对接和分子动力学研究

类泛素化是一种蛋白质翻译后修饰,其异常会导致神经退行性疾病和多种肿瘤的发生,因此它被视为有希望的抗肿瘤靶标.研究表明,抑制DCN1-UBE2M相互作用可选择性阻遏类泛素化.本文基于哌啶基脲类DCN1-UBE2M相互作用抑制剂进行3D-QSAR、分子对接和分子动力学模拟研究.利用3D-QSAR中的CoMFA和CoMSIA...     

由3D-QSAR、分子对接和分子动力学模拟研究吲唑类化合物与PI3Kδ抑制剂的相互作用

磷酸肌醇3-激酶δ(PI3Kδ)参与慢性阻塞性肺疾病的炎性过程并且被鉴定为一个新的潜在治疗靶点。本文采用三维定量构效关系(3D-QSAR)、分子对接和分子动力学方法研究了47个吲唑类化合物与P13Kδ激酶的相互作用,并建立了相应的模型。其中,比较分子场分析(CoMFA)模型q~2=0.719,r~2=0.972;比较分子相似性指数分析(CoMSIA)模型q~2=0.649,r~2=0.983,表明所建的QSAR模型具有稳定可靠的预测能力。CoMFA和CoMSIA等势图形象地描述了不同的场效应对活性的影响,其中立体场、疏水场及氢键受体场对活性有较大的贡献。接着采用分子对接探索小分子化合物与P13Kδ的结合模式,结合模式显示吲唑类化合物主要通过氢键作用与疏水作用与P13Kδ紧密结合,并且通过分子动力学模拟进一步验证了对接结果。最后根据等势图、对接模式和分子动力学模拟获取的信息设计了8个化合物,研究表明它们均能与PI3Kδ较好结合。     

拟南芥TIR1与生长素IAA相互作用的分子对接及分子动力学研究

基于最新得到的拟南芥运输抑制剂响应蛋白质1(TIR1)与吲哚乙酸(IAA)复合物的晶体结构, 使用分子对接方法和分子动力学方法对TIR1与生长素IAA相互作用的方式进行了研究. 分子对接结果表明, 通过逐级考察辅酶InsP₆和中心水分子的影响, 发现辅酶InsP₆和中心水分子对生长素IAA正确结合到活性位点有重要作用. 分子动力学结果表明, 复合物体系在整个模拟过程中较为稳定, 2个水分子相继作为中心水分子与生长素IAA形成了稳定的氢键作用, IAA与活性位点处残基的相互作用与晶体结构相比略有差异.     

HIV-1整合酶链转移抑制剂的3D-QSAR、分子对接和分子动力学模拟研究

为了获得高活性、结构新颖的整合酶链转移(INST)抑制剂,本文采用Co MFA和Co MSIA两种方法对32个萘啶类INST抑制剂进行了三维定量构效关系研究,并建立了相关模型,其交叉验证系数分别为q~2=0. 809和q~2=0. 816,拟合验证系数分别为r~2=0. 998和r~2=0. 981,表明所建立的模型是可靠的且具有一定的预测能力。利用分子对接探讨小分子化合物与INST蛋白的相互作用模式,结果表明,萘啶类化合物主要通过疏水作用和氢键作用与INSTIs蛋白结合。最后通过分子动力学模拟进一步验证对接结果发现,对接的结合模式与分子动力学模拟得到的结果是一致的。本研究获得的综合模型和推论可以为开发有效的HIV INSTIs提供重要的理论信息。     

芬太尼类化合物与阿片μ受体相互作用的分子对接与分子动力学模拟

采用分子对接和分子动力学(MD)模拟方法研究了芬太尼类化合物与阿片μ受体的相互作用机制.先用AutoDock4.0程序将芬太尼类化合物对接到同源模建的阿片μ受体结构中,再用GROMACS程序包在水溶液体系中分别对12个芬太尼激动剂和阿片μ受体蛋白复合物进行了MD模拟研究,优化对接复合物的结构,最后利用MM-PBSA方法,在APBS程序中计算芬太尼类衍生物与阿片μ受体的结合自由能,计算出的受体配合物结合常数(Ki)与其实验值吻合较好,并预测了化合物的活性排序.结果表明,复合物蛋白结构与空载受体蛋白结构有较大差异,特别是胞内区IL2、IL3和跨膜区段TM4骨架构象变化较大,不同的化合物对受体结构影响也有差异,活性较好的化合物会增加蛋白特定区域结构的柔性.芬太尼类化合物可能是通过和受体结合后诱导阿片μ受体构象转变为活性构象,引起一系列的信号传导激活G蛋白,从而引发生理效应.     

雪卡毒素毒性机理的分子对接及分子动力学研究

采用分子对接和分子动力学方法,研究了雪卡毒素与其毒性作用靶点之一钠通道的结合模式,并与钠通道阻滞剂奎尼丁比较.研究结果表明,雪卡毒素、奎尼丁与钠通道作用方式有所不同.分子动力学模拟表明,对接受体-配体复合物体系在2.5 ns的模拟过程中稳定.奎尼丁在钠通道中央与GLU1784,THR1858各形成1个稳定氢键,吡啶环与...     

3C-like蛋白酶抑制剂的构效关系、分子对接和分子动力学

3C-like蛋白酶是中东呼吸综合征冠状病毒（MERS-CoV）等其它冠状病毒的繁殖过程中极为重要的蛋白酶。它已成为人类在抗冠状病毒领域中的研究热点。本文基于计算生物学方法对与MERS-CoV同属的蝙蝠冠状病毒HKU4（HKU4-CoV）的43个肽类3C-like蛋白酶抑制剂分子,建立三维定量构效关系（3D-QSAR）模型。在基于配体叠合的基础上,发现比较分子相似性指数分析法（CoMSIA）中的四个场组合（位阻场、静电场、氢键供体场与氢键受体场）为最优的模型（Q²=0.522,R_ncv²=0.996,R_pre²=0.904;Q²：交叉验证相关系数,R_ncv²：非交叉验证相关系数,R_pre²：验证集分子的预测值相关系数）,并借助该模型通过分子对接（docking）与分子动力学（MD）方法阐明了配受体结合作用。实验结果表明：（1）基于最优的CoMSIA模型基础上的三维等势图形象地说明了分子基团的位阻作用、静电作用、氢键供体与氢键受体作用对分子生物活性的影响;（2）分子对接研究结果显示了疏水性以及结晶水、氨基酸His166和Glu169在配体和受体结合过程中产生重要作用;（3）分子动力学模拟进一步验证了分子对接模型的可靠性,并发现了两个新的关键氨基酸Ser24与Gln192,它们与配体产生了两个较强的氢键。此外,根据这些结果,一些新的具有潜在抑制活性的肽类化合物作为3C-like蛋白酶抑制剂被获得。以上结果能够帮助深入了解3C-like蛋白酶与肽类抑制剂的作用机理,并且能够为今后的抗MERS-CoV药物设计提供有价值的参考。     

基于分子对接的thanatin与NDM-1分子动力学模拟研究

耐碳青霉烯类抗生素的超级细菌给人类健康带来了严重威胁,其所携带的金属 β-内酰胺酶编码基因是耐药性的主要来源。NDM-1作为其中传播最广、活性最强的 β-内酰胺酶,其抑制剂的研发刻不容缓。具有广谱作用的抗菌肽thanatin对NDM-1展现出了较好的抑制效果,但抑制机理并不清楚。本文使用HPEPDOCK与Rosetta FlexPepDock服务器,将thanatin与NDM-1进行了分子对接,并使用Desmond软件包对对接模型进行了分子动力学模拟。结果表明,thanatin与NDM-1活性中心的Zn2+ 并无直接相互作用,而作为竞争性抑制剂结合于NDM-1的活性口袋,阻止抗生素分子进入活性口袋与Zn2+ 结合,从而抑制NDM-1的水解活性。本文为研发有效的NDM临床抑制剂探索了可行的方法。     

基于虚拟筛选和分子动力学模拟发现新型ULK1抑制剂

Unc-51样自噬激活激酶1（unc-51-like autophagy activating kinase 1,ULK1）作为自噬启动的重要调控因子,是肿瘤治疗的关键靶点之一。首先,以已知ULK1抑制剂为基础构建药效团模型,通过药效团模型筛选、分子对接以及分子力学广义波恩表面积（Molecular Mechanics/Generalized Born Surface Area,MM/GBSA）结合自由能计算等方法,对含有52万多个类药性小分子的数据库进行虚拟筛选,得到具有较高理论亲和力的化合物。随后,50ns的分子动力学模拟验证了蛋白质-配体复合物结合的稳定性,最后10ns的平均结合自由能的计算研究进一步验证了配体的结合能力。结果表明,6个化合物（F5258-0159、F3407-0428、F0529-1100、F0696-3531、F3222-5280、F6525-5596）具有骨架新颖、分子对接分数和结合自由能数值优异及与ULK1的结合状态稳定等特点,可以作为新型潜在的ULK1抑制剂用于肿瘤治疗的研究,也为新型ULK1抑制剂的设计和研发提供新的研究思路。     

Exploring Amantadine Derivatives as Urease Inhibitors: Molecular Docking and Structure–Activity Relationship (SAR) Studies

This article describes the design and synthesis of a series of novel amantadine-thiourea conjugates (3a–j) as Jack bean urease inhibitors. The synthesized hybrids were assayed for their in vitro urease inhibition. Accordingly, N-(adamantan-1-ylcarbamothioyl)octanamide (3j) possessing a 7-carbon alkyl chain showed excellent activity with IC₅₀ value 0.0085 ± 0.0011 µM indicating that the long alkyl chain plays a vital role in enzyme inhibition. Whilst N-(adamantan-1-ylcarbamothioyl)-2-chlorobenzamide (3g) possessing a 2-chlorophenyl substitution was the next most efficient compound belonging to the aryl series with IC₅₀ value of 0.0087 ± 0.001 µM. The kinetic mechanism analyzed by Lineweaver–Burk plots revealed the non-competitive mode of inhibition for compound 3j. Moreover, in silico molecular docking against target protein (PDBID 4H9M) indicated that most of the synthesized compounds exhibit good binding affinity with protein. The compound 3j forms two hydrogen bonds with amino acid residue VAL391 having a binding distance of 1.858 Å and 2.240 Å. The interaction of 3j with amino acid residue located outside the catalytic site showed its non-competitive mode of inhibition. Based upon these results, it is anticipated that compound 3j may serve as a lead structure for the design of more potent urease inhibitors.     

螺环吲哚类MDM2抑制剂的分子对接、定量构效关系和分子动力学模拟

采用分子对接、三维定量构效关系(3D-QSAR)和分子动力学方法研究了21个螺环吲哚类化合物与MDM2蛋白的相互作用, 并建立了相关预测模型. 比较分子场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)模型的交互验证相关系数q²分别为0.573 和0.651, 非交互验证相关系数r²分别为0.948和0.980. 分子对接得到的结合模式与分子动力学模拟得到的结果一致, 结合模式表明该类螺环吲哚化合物主要通过疏水相互作用和氢键与MDM2结合. 基于上述相互作用模型设计并合成了6个新结构螺环吲哚化合物, 并在MDM2高表达的前列腺癌LNCaP细胞株上测定其活性, 结果表明化合物5, 6的半数抑制浓度均低于1μg·mL^-1, 可作为新的抗肿瘤药物先导化合物进一步深入研究. 本研究对以MDM2为靶点的新结构螺环吲哚类抑制剂的开发提供了理论和实验依据.     

Study of Endogen Substrates,Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics

Multidrug resistance protein-4 (MRP4) belongs to the ABC transporter superfamily and promotes the transport of xenobiotics including drugs. A non-synonymous single nucleotide polymorphisms (nsSNPs) in the ABCC4 gene can promote changes in the structure and function of MRP4. In this work, the interaction of certain endogen substrates, drug substrates, and inhibitors with wild type-MRP4 (WT-MRP4) and its variants G187W and Y556C were studied to determine differences in the intermolecular interactions and affinity related to SNPs using protein threading modeling, molecular docking, all-atom, coarse grained, and umbrella sampling molecular dynamics simulations (AA-MDS and CG-MDS, respectively). The results showed that the three MRP4 structures had significantly different conformations at given sites, leading to differences in the docking scores (DS) and binding sites of three different groups of molecules. Folic acid (FA) had the highest variation in DS on G187W concerning WT-MRP4. WT-MRP4, G187W, Y556C, and FA had different conformations through 25 ns AA-MD. Umbrella sampling simulations indicated that the Y556C-FA complex was the most stable one with or without ATP. In Y556C, the cyclic adenosine monophosphate (cAMP) and ceefourin-1 binding sites are located out of the entrance of the inner cavity, which suggests that both cAMP and ceefourin-1 may not be transported. The binding site for cAMP and ceefourin-1 is quite similar and the affinity (binding energy) of ceefourin-1 to WT-MRP4, G187W, and Y556C is greater than the affinity of cAMP, which may suggest that ceefourin-1 works as a competitive inhibitor. In conclusion, the nsSNPs G187W and Y556C lead to changes in protein conformation, which modifies the ligand binding site, DS, and binding energy.     

New Triazinoindole Bearing Benzimidazole/Benzoxazole Hybrids Analogs as Potent Inhibitors of Urease: Synthesis,In Vitro Analysis and Molecular Docking Studies

Twenty-four analogs based on triazinoindole bearing benzimidazole/benzoxazole moieties (1–25) were synthesized. Utilizing a variety of spectroscopic methods, including ¹H-, ¹³C-NMR, and HREI-MS, the newly afforded compounds (1–25) were analyzed. The synthesized analogs were tested against urease enzyme (in vitro) as compared to the standard thiourea drug. All triazinoindole-based benzimidazole/benzoxazole analogs (1–25) exhibited moderate to excellent inhibition profiles, having IC₅₀ values of 0.20 ± 0.01 to 36.20 ± 0.70 μM when evaluated under the positive control of thiourea as a standard drug. To better understand the structure–activity relationship, the synthesized compounds were split into two groups, “A” and “B.” Among category “A” analogs, analogs 8 (bearing tri-hydroxy substitutions at the 2,4,6-position of aryl ring C) and 5 (bearing di-hydroxy substitutions at the 3,4-position of aryl ring C) emerged as the most potent inhibitors of urease enzyme and displayed many times more potency than a standard thiourea drug. Besides that, analog 22 (which holds di-hydroxy substitutions at the 2,3-position of the aryl ring) and analog 23 (bearing ortho-fluoro substitution) showed ten-fold-enhanced inhibitory potential compared to standard thiourea among category “B” analogs. Molecular docking studies on the active analogs of each category were performed; the results obtained revealed that the presence of hydroxy and fluoro-substitutions on different positions of aryl ring C play a pivotal role in binding interactions with the active site of the targeted urease enzyme.     

A Calorimetric Study on the Interaction of Zinc and Cadmium Ions with Jack Bean Urease

A thermodynamic study on the interaction of Jack bean urease, JBU, with Zn²⁺ and Cd²⁺ ions was studied by isothermal titration calorimetry (ITC) at 290, 300 and 310 K in 30 mmol/L Tris buffer solution, pH 7.0. The heats of JBU+Zn²⁺ and JBU+ ²⁺ interactions are reported and analyzed in terms of the extended solvation theory. It was indicated that there is a set of 12 identical and non‐interacting binding sites for Zn²⁺ and Cd²⁺ ions. The interactions of Zn²⁺ and Cd²⁺ ions with JBU are exothermic and both enthalpy and entropy driven. The association equilibrium constants for JBU+Zn²⁺ complexes are 4118.20, 3354.70 and 2790.62 L·mol^?1 at 290, 300 and 310 K respectively. The association equilibrium constants for JBU+Cd²⁺ interactions are 2831.6 and 2386.28 L· ^?1 at 300 and 310 K, respectively.     

Design of Novel IRAK4 Inhibitors Using Molecular Docking,Dynamics Simulation and 3D-QSAR Studies

Treatment of several autoimmune diseases and types of cancer has been an intense area of research over the past two decades. Many signaling pathways that regulate innate and/or adaptive immunity, as well as those that induce overexpression or mutation of protein kinases, have been targeted for drug discovery. One of the serine/threonine kinases, Interleukin-1 Receptor Associated Kinase 4 (IRAK4) regulates signaling through various Toll-like receptors (TLRs) and interleukin-1 receptor (IL1R). It controls diverse cellular processes including inflammation, apoptosis, and cellular differentiation. MyD88 gain-of-function mutations or overexpression of IRAK4 has been implicated in various types of malignancies such as Waldenström macroglobulinemia, B cell lymphoma, colorectal cancer, pancreatic ductal adenocarcinoma, breast cancer, etc. Moreover, over activation of IRAK4 is also associated with several autoimmune diseases. The significant role of IRAK4 makes it an interesting target for the discovery and development of potent small molecule inhibitors. A few potent IRAK4 inhibitors such as PF-06650833, RA9 and BAY1834845 have recently entered phase I/II clinical trial studies. Nevertheless, there is still a need of selective inhibitors for the treatment of cancer and various autoimmune diseases. A great need for the same intrigued us to perform molecular modeling studies on 4,6-diaminonicotinamide derivatives as IRAK4 inhibitors. We performed molecular docking and dynamics simulation of 50 ns for one of the most active compounds of the dataset. We also carried out MM-PBSA binding free energy calculation to identify the active site residues, interactions of which are contributing to the total binding energy. The final 50 ns conformation of the most active compound was selected to perform dataset alignment in a 3D-QSAR study. Generated RF-CoMFA (q² = 0.751, ONC = 4, r² = 0.911) model revealed reasonable statistical results. Overall results of molecular dynamics simulation, MM-PBSA binding free energy calculation and RF-CoMFA model revealed important active site residues of IRAK4 and necessary structural properties of ligand to design more potent IRAK4 inhibitors. We designed few IRAK4 inhibitors based on these results, which possessed higher activity (predicted pIC₅₀) than the most active compounds of the dataset selected for this study. Moreover, ADMET properties of these inhibitors revealed promising results and need to be validated using experimental studies.     

Molecular Docking and Molecular Dynamics Studies Reveal Secretory Proteins as Novel Targets of Temozolomide in Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is a tumor of glial origin and is the most malignant, aggressive and prevalent type, with the highest mortality rate in adult brain cancer. Surgical resection of the tumor followed by Temozolomide (TMZ) therapy is currently available, but the development of resistance to TMZ is a common limiting factor in effective treatment. The present study investigated the potential interactions of TMZ with several secretory proteins involved in various molecular and cellular processes in GBM. Automated docking studies were performed using AutoDock 4.2, which showed an encouraging binding affinity of TMZ towards all targeted proteins, with the strongest interaction and binding affinity with GDF1 and SLIT1, followed by NPTX1, CREG2 and SERPINI, among the selected proteins. Molecular dynamics (MD) simulations of protein–ligand complexes were performed via CABS-flex V2.0 and the iMOD server to evaluate the root-mean-square fluctuations (RMSFs) and measure protein stability, respectively. The results showed that docked models were more flexible and stable with TMZ, suggesting that it may be able to target putative proteins implicated in gliomagenesis that may impact radioresistance. However, additional in vitro and in vivo investigations can ascertain the potential of the selected proteins to serve as novel targets for TMZ for GBM treatment.     

自组装的分子动力学模拟

简要回顾了近年来国内外分子动力学模拟自组装的研究,对已报道的建模方法、可视化表现以及相关应用略作概述,并以此为基础对自组装过程的分子动力学模拟研究所面临的问题和尚需深入的内容进行了讨论。基于自组装、相变和涨落的固有联系,提出了以研究波动为手段,和以频率相关热容为研究对象的探索方向。希望能够为分子动力学模拟推动自组装研究提供有益的参考。