通常情况下，我们研究药物的时候，一般是老药新用，也就是已知药物发现新的治疗其他疾病的用途；或者在相关的网站上进行检索（后面我会介绍几个检索网址供大家参考）；还有一种是对已知化合物进行结构改造，首先可以选择感兴趣的化合物进行结构改造：

例如：

 

最终新旧结构的差异

 

得出新的化合物，首先在细胞层面上进行验证，看对细胞的毒性方面的作用。

 

再次，在结构上进行解释：

 

       这篇文献的话，做的比较浅显，只能发很低的分数，要想发更高的分数，当然是对药物分子机制进行更深一步的探索啦！

       接下来我们看下面这一篇文献，到底是怎么对药物分子机制进行研究的！

 

Fig. 1. GZD856 exhibits antiproliferative activity against a panel of lung cancer cells in vitro. (A) Chemical structure of GZD856. (B) PDGFR expression levels in twelve lung cancer cell lines were examined by western blotting. (C) Inhibition of PDGFR kinase activity by GZD856 was evaluated using an ELISA-based enzymatic assay. (D) Profiling the GZD856 sensitivity of tumor cell lines with various lung cancer cell genotypes。

 

Fig. 2. GZD856 suppresses the PDGFRα/β signaling pathway in H1703 and A549 cells.(A) GZD856 inhibited the PDGFR signaling pathway in the A549 cell line. (B) GZD856 inhibited the PDGFR signaling pathway in the H1703 cell line. The effect of GZD856 on the expression of pPDGFRα or pPDGFRβ, pSTAT3, pAKT and pERK1/2 was tested after the cells were treated with 0.1 μM to 10 μM GZD856 for 6.0 h. Representative results are shown, and similar results were obtained in three independent trials.

 

Fig. 3. GZD856 induces G0/G1 cell cycle arrest and apoptosis in H1703 but not A549 cells. (A) A549 and H1703 cells were treated with 0.3, 1 or 3 μM GZD856 for 24 h before DNA labeling with propidium iodide and cell cycle analysis by flow cytometry. (B) A549 and H1703 cells were treated with 0.3, 1 or 3 μM GZD856 for 48 h before DNA labeling with Annexin V and 7-AAD and cell cycle analysis by flow cytometry. (C) The effect of GZD856 on the expression of CDK4, Cyclin D2, CDK2, Cyclin E, Caspase-9, Caspase-3 and PARP was tested by western blotting. The cells were treated with 0.1 μM–10 μM GZD856 for 24 h. Representative results are shown, and similar results were obtained in three other independent trials .

 

Fig. 4. GZD856 potently inhibits tumor growth in H1703 and A549 xenograft Models. CB17-SCID mice xenografted with either H1703 cells or A549 cells were treated with vehicle or GZD856 (10, 30 mg/kg, po, qd) for 16 days. The tumor growth curves are plotted in (A) and (C). Tumor weights on day 16 are shown in (B) and (D) (n = 6 per group). (E) HE, Masson and TUNEL staining of A549 tumors harvested from mice treated with GZD856 or vehicle for 16 days. Representative images of sections stained with antibodies to detect α-SMA (stromal myofibroblasts) and Masson to detect collagen secreted by stromal myofibroblasts. (F) GZD856 suppressed signaling in vivo.

 

Fig. 5. GZD856 suppresses the migration and metastasis of A549 cells in vitro and in vivo. (A) GZD856 efficiently inhibited proliferation and metastasis in an orthotopic lung cancer model using A549 cells expressing luciferase. (B) HE staining showed that GZD856 inhibited the growth of A549 cells in lung and decreased the size and number of metastatic colonies in the liver and brain. (C) Quantification of the images in A. (D) GZD856 inhibited colony formation by A549 cells in vitro. Quantitative results are shown in F. (E) GZD856 inhibited the migration of A549 cells in vitro. Quantitative results are shown in G. Representative data and corresponding quantitative analyses are shown.

本文除做了药物对细胞的毒性实验，还在体内对其所研究的药物进行了更深入的机制研究，使其分数提高了不少！
其要点：不需合成，但要有创新的靶点或创新的化合物。


       下面就来安利几个查询药物的网址：想研究药物分子机制方面的小伙伴们，一定要查看，不然有可能会错过几个亿哦！

1:drugbank:
网址：https://www.drugbank.ca/

DrugBank数据库是混合的生物信息学和化学信息学资源，其将详细的药物（即化学，药理学和药物）数据与综合药物靶标（即序列，结构和途径）信息相结合。 该数据库包含7,800多种药物，还包含广泛的SNP药物数据，可用于药物基因组学研究。

2:Therapeutic Target DB
网址：https://db.idrblab.org/ttd/

Therapeutic Target DB 是一种药物数据库，旨在提供关于文献中描述的已知治疗性蛋白质和核酸靶标，靶向疾病状况，途径信息以及针对每种靶标的相应药物/配体的信息。

3：PharmGKB
网址：https://www.pharmgkb.org/

PharmGKB数据库是遗传，基因组，分子和细胞表型数据以及参与药物基因组学研究研究的人员的临床信息的中央存储库。 数据包括但不限于心血管，肺部，癌症，通路，代谢和转运蛋白结构域的临床和基础药代动力学和药物基因组学研究。 其目的是帮助研究人员了解个体间的遗传变异如何促成对药物反应的差异。

除了上面的数据库，还有其他与药物分子机制研究相关的数据库：例如疾病与生理学数据库、代谢途径的数据库以及全面的代谢组学数据库等，要是想深入研究药物分子作用机制，快快联系我们吧！

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