结合分子相似性、药效团和分子对接筛选新的HIV-1蛋白酶抑制剂

结合分子相似性、药效团和分子对接建立兼顾计算效率和预测准确度的HIV-1蛋白酶抑制剂筛选方法。首先通过对现有HIV-1蛋白酶抑制剂分子进行相似性分析,选取代表性的HIV-1蛋白酶抑制剂作为模板分子,构建和优化药效团模型,并从1万个化合物中优先筛选出500个化合物。而后采用分子对接方法进一步考察化合物与HIV-1蛋白酶结合情况,得到4个新的活性候选化合物,并进行其结合自由能计算和抗突变性分析。结果表明新候选化合物ST025723和HIV-1蛋白酶表现出较好的相互作用和抗突变性,具有深入研究的价值,同时也证明分子相似性、药效团和分子对接相结合能够快速有效地发现新颖活性候选化合物。     

基于天然产物的蛋白酪氨酸磷酸酶1B 抑制剂的虚拟筛选

蛋白酪氨酸磷酸酶1B(protein tyrosine phosphatase 1B,PTP1B)是治疗Ⅱ型糖尿病的靶点之一,筛选PTP1B抑制剂具有十分重要的意义.本文采用分子对接虚拟筛选方法,构建共含有42 296个小分子的天然产物库,分别与PTP1B靶点蛋白进行分子对接,以原配体的结合能量为阈值,经过三轮筛选选取打分值高于阈值的小分子进行药代动力学参数和毒性参数预测,最终筛选出3个PTP1B抑制剂,对苯醌类化合物7、异香豆素类衍生物10和Clavepictine类似物11.结合方式研究表明,3个候选抑制剂类药性良好,均具有较好的PTP1B抑制活性,其中化合物10和11的PTP1B抑制活性未见报道.对化合物10进行体外抑制活性检测,其IC50为(74.58±1.23)μmol/L,可作为潜在Ⅱ型糖尿病治疗药物.     

In silico studies on potential MCF-7 inhibitors: a combination of pharmacophore and 3D-QSAR modeling,virtual screening,molecular docking,and pharmacokinetic analysis

Gallic acid and its derivatives exhibit a diverse range of biological applications, including anti-cancer activity. In this work, a data-set of forty-six molecules containing the galloyl moiety, and known to show anticarcinogenic activity against the MCF-7 human cancer cell line, have been chosen for pharmacophore modeling and 3D-Quantitative Structure Activity Relationship (3D-QSAR) studies. A tree-based partitioning algorithm has been used to find common pharmacophore hypotheses. The QSAR model was generated for three, four, and five featured hypotheses with increasing PLS factors and analyzed. Results for five featured hypotheses with three acceptors and two aromatic rings were the best out of all the possible combinations. On analyzing the results, the most robust (R^2?=?.8990) hypothesis with a good predictive power (Q^2?=?.7049) was found to be AAARR.35. A good external validation (R² = .6109) was also obtained. In order to design new MCF-7 inhibitors, the QSAR model was further utilized in pharmacophore-based virtual screening of a large database. The predicted IC₅₀ values of the identified potential MCF-7 inhibitors were found to lie in the micromolar range. Molecular docking into the colchicine domain of tubulin was performed in order to examine one of the probable mechanisms. This revealed various interactions between the ligand and the active site protein residues. The present study is expected to provide an effective guide for methodical development of potent MCF-7 inhibitors.     

A common feature-based 3D-pharmacophore model generation and virtual screening: identification of potential PfDHFR inhibitors

A four-feature 3D-pharmacophore model was built from a set of 24 compounds whose activities were reported against the V1/S strain of the Plasmodium falciparum dihydrofolate reductase (PfDHFR) enzyme. This is an enzyme harboring Asn51Ile + Cys59Arg + Ser108Asn + Ile164Leu mutations. The HipHop module of the Catalyst program was used to generate the model. Selection of the best model among the 10 hypotheses generated by HipHop was carried out based on rank and best-fit values or alignments of the training set compounds onto a particular hypothesis. The best model (hypo1) consisted of two H-bond donors, one hydrophobic aromatic, and one hydrophobic aliphatic features. Hypo1 was used as a query to virtually screen Maybridge2004 and NCI2000 databases. The hits obtained from the search were subsequently subjected to FlexX and Glide docking studies. Based on the binding scores and interactions in the active site of quadruple-mutant PfDHFR, a set of nine hits were identified as potential inhibitors.     

靶向基质金属蛋白酶14类血红素结构域特异活性位点的确定及反义肽虚拟筛选

目的:确定基质金属蛋白酶14(MMP-14)类血红素结构域(HPX14)特异活性位点,虚拟筛选获得能与HPX14特异结合的短肽。方法:用metaPocket预测HPX14的活性口袋,多序列比对分析活性口袋的氨基酸残基特异性;基于M-I和R-B理论设计以特异活性位点为正义肽的反义肽库,并进行虚拟筛研究及结合特异性确定。结果:生物信息学分析确定了KGRGLTD为HPX14的特异活性位点,并构建了其1036条反义肽;通过2轮虚拟筛选,获得10条得分居前的与HPX14结合较好的反义肽,它们与HPX14具有较高的亲和力,并可能影响MMP-14同源二聚体的形成和MMP-14活性的抑制;VSETAPF、IGEPPPF是对接打分最好的2条短肽,与HPX14的结合具有特异性。结论:KGRGLTD是HPX14的特异活性位点,虚拟筛选得到的VSETAPF、IGEPPPF等反义肽与HPX14具有较高的亲和力,这为基于MMP-14的HPX结构域的靶向小分子多肽先导药物的发现提供了重要的前期工作基础与新思路。     

Virtual Screening of Indonesian Herbal Database as HIV-1 Protease Inhibitor

HIV-1 (Human immunodeficiency virus type 1)׳s infection is considered as one of most harmful disease known by human, the survivability rate of the host reduced significantly when it developed into AIDS. HIV drug resistance is one of the main problems of its treatment and several drug designs have been done to find new leads compound as the cure. In this study, in silico virtual screening approach was used to find lead molecules from the library or database of natural compounds as HIV-1 protease inhibitor. Virtual screening against Indonesian Herbal Database with AutoDock was performed on HIV-1 protease. From the virtual screening, top ten compounds obtained were 8-Hydroxyapigenin 8-(2",4"-disulfatoglucuronide), Isoscutellarein 4''-methyl ether, Amaranthin, Torvanol A, Ursonic acid, 5-Carboxypyranocyanidin 3-O-(6"-O-malonyl-beta-glucopyranoside), Oleoside, Jacoumaric acid, Platanic acid and 5-Carboxypyranocyanidin 3-O-beta-glucopyranoside.     

Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing

Abstract

Histone deacetylases (HDACs), a critical family of epigenetic enzymes, has emerged as a promising target for antitumor drugs. Here, we describe our protocol of virtual screening in identification of novel potential HDAC inhibitors through pharmacophore modeling, 3D-QSAR, molecular docking and molecular dynamics (MD) simulation. Considering the limitation of current virtual screening works, drug repurposing strategy was applied to discover druggable HDAC inhibitor. The ligand-based pharmacophore and 3D-QSAR models were established, and their reliability was validated by different methods. Then, the DrugBank database was screened, followed by molecular docking. MD simulation (100?ns) was performed to further study the stability of ligand binding modes. Finally, results indicated the hit DB03889 with high in silico inhibitory potency was suitable for further experimental analysis.

Communicated by Ramaswamy H. Sarma     

The relationship of calcium and parathyroid hormone in their effect on heart cells

Parathyroid hormone (PTH), the plasma concentration of which is raised in uremia, has been suggested as one of the agents responsible for the myocardial changes commonly seen in uremia. The effect of intact [1–84] PTH on rat heart cells grown in tissue culture has been studied. Addition of the hormone to the media significantly stimulated beating rate. The stimulation was directly proportional to the amount of PTH in the medium. Excessively high concentration of PTH caused immediate cessation of the beating, which was reversed by the addition of calcium to the medium. The extent of stimulation by PTH was inversely proportional to the calcium concentrations in the medium. Isoproterenol and phenylephrine at excessively high concentrations in the medium did not mimic the PTH effect either alone or together with PTH. When beating ceased due to verapamil the effect was not reversed by the addition of calcium to the medium.Calcium added to the myocytes seen after beating ceased reversed the effect and the cells started to beat again. Cells kept for a longer period in the arrested state were not revived by the addition of calcium.