Identification of novel, less toxic PTP-LAR inhibitors using in silico strategies: pharmacophore modeling, SADMET-based virtual screening and docking
Identification of novel, less toxic PTP-LAR inhibitors using in silico strategies: pharmacophore modeling, SADMET-based virtual screening and docking
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DOI：
10.1007/s00894-011-1037-0
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发表时间：
2012-01-01
影响因子：
2.2
通讯作者：
Sobhia, M. Elizabeth
中科院分区：
文献类型：
--
作者：
Ajay, Dara;Sobhia, M. Elizabeth
人白细胞抗原相关（PTP-LAR）是一种受体样跨膜磷酸酶，是糖尿病、肥胖和癌症的潜在靶点。在本研究中，通过一系列的计算机策略（药效团定位、3D数据库搜索、SADMET筛选、对接和毒性研究）鉴定出8种新的无毒PTP-LAR抑制剂。采用两种方法生成了20种不同的药效团假说；最好的假设2包含三个氢键受体(A)，一个环芳香(R)和一个疏水脂肪族(Z)特征。该假设被用于筛选来自多个数据库的分子，如Specs、IBS、MiniMaybridge、NCI和内部PTP抑制剂数据库。为了克服与磷酸酶相关的一般生物利用度问题，通过Lipinski's rule of five和SADMET性质对获得的命中进行过滤，并使用可用的晶体结构1LAR进行分子对接研究。这些对接研究提示了LAR抑制所需的配体结合模式和相互作用。对接分析还显示，具有异喹啉或萘支架的磺脲类衍生物是潜在的LAR药物。通过配体药效团作图研究进一步验证了筛选方案，结果表明上述相互作用确实至关重要，并且可以推定筛选的分子具有强大的抑制活性。
Human leukocyte antigen-related (PTP-LAR) is a receptor-like transmembrane phosphatase and a potential target for diabetes, obesity and cancer. In the present study, a sequence of in silico strategies (pharmacophore mapping, a 3D database searching, SADMET screening, and docking and toxicity studies) was performed to identify eight novel nontoxic PTP-LAR inhibitors. Twenty different pharmacophore hypotheses were generated using two methods; the best (hypothesis 2) consisted of three hydrogen-bond acceptor (A), one ring aromatic (R), and one hydrophobic aliphatic (Z) features. This hypothesis was used to screen molecules from several databases, such as Specs, IBS, MiniMaybridge, NCI, and an in-house PTP inhibitor database. In order to overcome the general bioavailability problem associated with phosphatases, the hits obtained were filtered by Lipinski's rule of five and SADMET properties and validated by molecular docking studies using the available crystal structure 1LAR. These docking studies suggested the ligand binding pattern and interactions required for LAR inhibition. The docking analysis also revealed that sulfonylurea derivatives with an isoquinoline or naphthalene scaffold represent potential LAR drugs. The screening protocol was further validated using ligand pharmacophore mapping studies, which showed that the abovementioned interactions are indeed crucial and that the screened molecules can be presumed to possess potent inhibitory activities.