摘要
为构建可靠的整合素αvβ3受体选择性拮抗剂的药效团模型并根据模型设计小分子活性化合物,选择对αvβ3受体具有较高抑制活性(IC50<110nmol·L-1)的4个类型(分别以酰胺、哌嗪、哌啶、γ-戊内酰胺为中间连接基)的30个化合物为训练集,利用Catalyst软件构建整合素αvβ3受体选择性拮抗剂药效团模型,并在数据库中寻找具有活性的母体结构,对母体结构进行修饰和改造及类药性分析得到先导化合物。得到的药效团模型相关系数好、预测能力高,可较准确的预测相关化合物的活性。优化模型含1个芳环中心(RA)、1个可阴离子化部位(NI)和2个疏水作用基(HP),其相关系数与权重值分别为:RMS=0.73,Correl=0.90,Weight=1.17,Config=14.00。所设计的目标化合物预测活性强且结构简单,易于合成,噻唑类为未见报道的一类母体结构化合物。
In order to generate a pharmacophore model of integrin αvβ3 receptor antagonists and design lead compounds which have potent and selective activity against αvβ3 receptor with the help of this model. Thirty compounds （four categories） with highly inhibitory activity against the integrin αvβ3 receptor （IC50 〈 110 nmol·L^-1）, amide, piperazine, piperidine, γ-valerolactam as the intermediate junction, separately, were selected as a training set to construct a three-dimensional pharmacophore models of integrin αvβ3 receptor antagonists with the Catalyst software. The best pharmacophore model of integrin αvβ3 receptor antagonists with RMS = 0.73, Correl = 0.90, Weight = 1.17, Config = 14.00 is found out, which consisting of four features： a neg ionizable core （NI）, two aliphatic hydrophobic core （HP） and an aromatic ring center （RA）. Some new and easily obtained compounds with fine ADME properties and highly potent activity against αvβ3 receptor were designed with the new pharmacophore models.
出处
《药学学报》
CAS
CSCD
北大核心
2009年第4期379-385,共7页
Acta Pharmaceutica Sinica
