基于特定靶点的药物虚拟筛选整体解决方案

前言

从2001-2018年数据看,全球在研新药数量保持持续增长态势,尤其是2011年以来,全球在研新药数量呈现明显增长势头。新药时代:传统小分子药、生物药(siRNA)、抗体药、细胞治疗,百花齐放。我们HYY一直秉承“携手基础科学与临床医学,共承医学转化的使命,追逐精准医学为目标,领航人类健康的伟大事业”的宗旨,推动医学转化的创新创业平台,为创新性社会发展贡献一份微薄之力!

01文献调研、模型构建

通过文献调研确定研究靶点,发现PDB数据库中有复合晶体结构,筛选备选PDB晶体结构,构建模型;确定活性位点 靶标抑制剂结合位点。

02小分子化合物库准备

多样性化合物库名称:Enamine、Chemdiv、Chembridge、lifechemicals、InterBioScreen、Specs、Maybridge 。

化合物库制备:类药性初筛

03Classifier model 分类模型构建

得到类靶向特定靶点的抑制剂小分子库。

04超级计算机筛选docking

软件名称:MGLTools和Autodock vina

版本号:1.5.6和1.1.2

MGLTools软件处理靶点蛋白结构;vina软件进行虚拟筛??;

第一步分子对接,根据cut off值得到1000-5000个Top hits。

05人工后期筛选

第二步聚类分析,人工挑选,得到50-100个Hits。

06激酶水平生物活性验证

激酶活性测试,初筛有活性的化合物,再筛选抑制率Top 5-10候选化合物,得出激酶水平IC50数据。

做到激酶水平IC50实验这里,目标文章IF 3分;

07细胞、蛋白及动物水平验证

再深入研究活性Top1-2的化合物做细胞实验,对通路蛋白的影响,细胞功能+动物实验等目标文章IF 5分以上。

08筛选部分总技术线路图

下面我们看一遍两篇文献案例

第一篇:Bioorganic & Medicinal Chemistry Letters 影响因子2.24

文章通过制定虚拟筛选策略得到4826个候选化合物,后面通过分子动力学模拟筛选及实验测定化合物活性得到4个具有抑制活性的小分子。

NO.1

Discovery of BRD4 bromodomain inhibitors by fragment-based

high-throughput docking

Bromodomains (BRDs) recognize acetyl-lysine modified histone tails mediating epigenetic processes. BRD4, a protein containing two bromodomains, has emerged as an attractive therapeutic target for several types of cancer as well as inflammatory diseases. Using a fragment-based in silico screening approach, we identified two small molecules that bind to the first bromodomain of BRD4 with lowmicromolar affinity and favorable ligand efficiency (0.37 kcal/mol per non-hydrogen atom), selectively over other families of bromodomains. Notably, the hit rate of the fragment-based in silico approach is about 10% as only 24 putative inhibitors, from an initial library of about 9 million molecules, were tested

in vitro.

图一:虚拟筛选流程图

图二:筛选得到4个活性抑制剂

表格展示活性化合物数据

图三、小分子作用机制展示

文章思路简洁,是虚拟筛选类的典型文章方案。

第二篇:Cancer Research 影响因子9.13

NO.2

Novel anticancer agents based on targeting the trimer interface of the PRL phosphatase

PRL oncoproteins are phosphatases overexpressed in numerous types of human cancer. Elevated levels of PRL associate with metastasis and poor clinical outcomes. In principle, PRL phosphatases offer appealing therapeutic targets, but they remain underexplored due to the lack of specific chemical probes. In this study, we address this issue by exploiting a unique property of PRL phosphatases, namely, that they may function as homotrimers. Starting from a sequential structure-based virtual screening and medicinal chemistry strategy, we identified Cmpd-43 and several analogs which disrupt PRL1 trimerization. Biochemical and structural analyses demonstrate that Cmpd-43 and its close analogs directly bind the PRL1 trimer interface and obstruct PRL1 trimerization. Cmpd-43 also specifically blocks the PRL1-induced cell proliferation and migration through attenuation of both ERK1/2 and Akt activity. Importantly, Cmpd-43 exerted potent anticancer activity both in vitro and in vivo in a murine xenograft model of melanoma. Our results validate a trimerization-dependent signaling mechanism for PRL and offer proof-of-concept for trimerization inhibitors as candidate therapeutics to treat PRL-driven cancers

文章通过虚拟筛选策略得到56候选化合物,进一步通过实验筛选得到3个化合物在细胞水平起到减少PRL1三聚体形成的作用。

进一步筛选与43号化合物的类似物,得到活性最好的化合物。

针对类似化合物1及43号化合物进行蛋白表达水平研究,以及相关通路蛋白的研究。

分子水平作用模式分析

43号化合物在黑色素瘤细胞系中展现抗癌活性。

后续体内实验验证43号化合物的抗癌活性。

本文针对筛选得到的化合物深入研究,解释作用机理,同时验证体内体外抗癌活性。

参考文献

1、Zhao H , Gartenmann L , Dong J , et al. Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking[J]. Bioorganic & Medicinal Chemistry Letters, 2014, 24(11):2493-2496.

2、Bai Y , Yu Z H , Liu S , et al. Novel anticancer agents based on targeting the trimer interface of the PRL phosphatase[J]. Cancer Research, 2016:0008-5472.CAN-15-2323.

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