6-氮杂甾醇类Ⅱ型5-α还原酶抑制剂的三维定量构效关系研究和虚拟筛选
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摘要
采用Topomer CoMFA对37个6-氮杂甾醇类抑制剂进行三维定量构效关系分析,新建模型的交互验证和拟合相关系数为q2=0.774,r2=0.965,结果表明模型具有良好的可信度和预测能力.将基于配体的Topomer search虚拟筛选、基于受体的分子对接虚拟筛选和基于3D-QSAR模型的分子活性预测等方法运用到新抑制剂的分级筛选,最终获得4个高活性的新抑制剂分子.新抑制剂的Surflex-dock结果显示6-氮杂甾醇类抑制剂与5AR-Ⅱ靶点的作用模式主要是氢键作用.MTT法生物学活性测试结果显示新抑制剂能显著抑制BPH-1细胞增殖,且抑制程度呈浓度依赖性.通过分子对接机理解释和细胞学实验的抑制前列腺增生活性测试,这两种研究方式相互验证,证明此虚拟筛选方法能够为治疗良性前列腺增生的新药设计提供有效候选化合物.
Three-dimensional quantitative structure-activity relationship analysis of 37 6-azasteroids inhibitors was carried out by Topomer CoMFA.The new model's cross validation and correlation coefficient were q2=0.774 and r2=0.965,respectively.The results show that the model has good prediction ability and reliability.Virtual screening based on Topomer search of ligand,virtual screening based on molecular docking of receptor and molecular activity prediction of 3 D-QSAR model were applied to the new inhibitor grading screening.Finally,four new inhibitor compounds with high activity were obtained.The Surflex-dock results of new inhibitors showed that the interaction pattern between 6-azosterol inhibitors and 5α-reductaseⅡtarget is mainly hydrogen bonding.The results of MTT assay show that the new inhibitor could significantly inhibit the proliferation of BPH-1 cells and the degree of inhibition is concentration dependent.Molecular docking mechanism interpretation and prostatic growth inhibition assay in cytological experiments are mutually validated.It is proved that this virtual screening method can provide effective candidate compounds for the treatment of benign prostatic hyperplasia.
Three-dimensional quantitative structure-activity relationship analysis of 37 6-azasteroids inhibitors was carried out by Topomer CoMFA.The new model's cross validation and correlation coefficient were q2=0.774 and r2=0.965,respectively.The results show that the model has good prediction ability and reliability.Virtual screening based on Topomer search of ligand,virtual screening based on molecular docking of receptor and molecular activity prediction of 3 D-QSAR model were applied to the new inhibitor grading screening.Finally,four new inhibitor compounds with high activity were obtained.The Surflex-dock results of new inhibitors showed that the interaction pattern between 6-azosterol inhibitors and 5α-reductaseⅡtarget is mainly hydrogen bonding.The results of MTT assay show that the new inhibitor could significantly inhibit the proliferation of BPH-1 cells and the degree of inhibition is concentration dependent.Molecular docking mechanism interpretation and prostatic growth inhibition assay in cytological experiments are mutually validated.It is proved that this virtual screening method can provide effective candidate compounds for the treatment of benign prostatic hyperplasia.
引文
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[17]Sangeethaa K,Sasikala R P,Meena K S.Pharmacophore modeling,virtual screening and molecular docking of ATPase inhibitors of HSP70[J].Comput Biol Chem,2017,70:164.
[18]Yan X Q,Wang Z C,Li Z,et al.Sulfonamide derivatives containing dihydropyrazole moieties selectively and potently inhibit MMP-2/MMP-9:design,synthesis,inhibitory activity and 3D-QSAR analysis[J].Bioorgan Med Chem,2015,25:4664.
[19]Sukriti G,Sonam B,Jaspreet K D,et al.Groupbased QSAR and molecular dynamics mechanistic analysis revealing the mode of action of novel piperidinone derived protein-protein inhibitors of p53-MDM2[J].J Mol Graph Model,2014,51:64.
[20]仝建波,江国艳,李园园,等.应用CoMFA研究抗菌肽的三维定量构效关系[J].原子与分子物理学报,2017,34:990.
[21]苗霞,梁桂兆.R基团搜索技术用于PTH类Tau蛋白抑制剂的分子设计[J].高等学校化学学报,2012,33:2263.
[22]左柯,杜文义,代田洋,等.肺炎克雷伯碳青霉烯酶与β-内酰胺酶抑制蛋白复合物的运动模式[J].四川大学学报:自然科学版,2017,54:585.
[23]Park E,Lee M Y,Seo C S,et al.Yongdamsagantang,a traditional herbal formula,inhibits cell growth through the suppression of proliferation and inflammation in benign prostatic hyperplasia epithelial-1cells[J].J Ethnopharmacol,2017,209:230.
[24]沈骏,郑茜茜,吴晓琴,等.油茶蒲提取物对人前列腺增生BPH-1细胞的抑制作用研究[J].现代食品科技,2015,31:6.
[2]Jena A K,Vasisht K,Sharma N,et al.Amelioration of testosterone induced benign prostatic hyperplasia by Prunus species[J].J Ethnopharmacol,2016,190:33.
[3]Kaplan A L,Hu C J,Morgentaler,et al.Testosterone therapy in men with prostate cancer[J].Eur Urol,2016,69:894.
[4]Nickel J C.Role of prostatic inflammation in the clinical presentation of benign prostatic hyperplasia[J].Eur Urol Suppl,2015,14:1459.
[5]Bechis S K,Otsetov A G,Ge R,et al.Personalized medicine for the management of benign prostatic hyperplasia[J].J Urology,2014,192:16.
[6]Bkowski T.Evaluation of the clinical indications,adverse drug reactions,and finasteride use in patients with benign prostatic hyperplasia in Poland[J].Pharmacol Rep,66:565.
[7]Lee S H,Chung B H,Kim C S,et al.Survey on benign prostatic hyperplasia distribution and treatment patterns for men with lower urinary tract symptoms visiting urologists at general hospitals in Korea:aprospective,noncontrolled,observational cohort study[J].Urol,2012,79:1379.
[8]Oelke M,Bachmann A,Descazeaud A,et al.EAUguidelines on the treatment and follow-up of nonneurogenic male lower urinary tract symptoms including benign prostatic obstruction[J].Eur Urol,2013,64:118.
[9]Marberger M,Harkaway R,Rosette J D L,et al.Optimising the medical management of benign prostatic hyperplasia[J].Eur Urol,2004,45:411.
[10]Nichola M B,Knighta T K,Wu J,et al.Evaluating use patterns of and adherence to medications for benign prostatic hyperplasia[J].J Urol,2009,181:2214.
[11]Mullinsa C,Luciac M S,Hayward S W.A comprehensive approach toward novel serum biomarkers for benign prostatic hyperplasia:the MPSA consortium[J].J Urol,2008,179:1243.
[12]Wiebe J P,Rivas M A,Mercogliano M F,et al.Progesterone-induced stimulation of mammary tumorigenesis is due to the progesterone metabolite,5α-dihydroprogesterone(5αP)and can be suppressed by the 5α-reductase inhibitor,finasteride[J].J Steroid Biochem,2015,149:27.
[13]Salvador J A,Pinto R M,Silvestre S M.Steroidal5α-reductase and 17α-hydroxylase/17,20-lyase(CYP17)inhibitors useful in the treatment of prostatic diseases[J].J Steroid Biochem,2013,137:199.
[14]Banday A H,Shameem S A,Jeelani S.Steroidal pyrazolines and pyrazoles as potential 5α-reductase inhibitors:synthesis and biological evaluation[J].Steroids,2014,92:13.
[15]Asati V,Bharti S K,Budhwani A K.3D-QSARand virtual screening studies of thiazolidine-2,4-dione analogs:Validation of experimental inhibitory potencies towards PIM-1kinase[J].J Mol Struct,2017,1133:278.
[16]Cao S D.QSAR,molecular docking studies of thiophene and imidazopyridine derivatives as polo-like kinase 1inhibitors[J].J Mol Struct,2012,1020:167.
[17]Sangeethaa K,Sasikala R P,Meena K S.Pharmacophore modeling,virtual screening and molecular docking of ATPase inhibitors of HSP70[J].Comput Biol Chem,2017,70:164.
[18]Yan X Q,Wang Z C,Li Z,et al.Sulfonamide derivatives containing dihydropyrazole moieties selectively and potently inhibit MMP-2/MMP-9:design,synthesis,inhibitory activity and 3D-QSAR analysis[J].Bioorgan Med Chem,2015,25:4664.
[19]Sukriti G,Sonam B,Jaspreet K D,et al.Groupbased QSAR and molecular dynamics mechanistic analysis revealing the mode of action of novel piperidinone derived protein-protein inhibitors of p53-MDM2[J].J Mol Graph Model,2014,51:64.
[20]仝建波,江国艳,李园园,等.应用CoMFA研究抗菌肽的三维定量构效关系[J].原子与分子物理学报,2017,34:990.
[21]苗霞,梁桂兆.R基团搜索技术用于PTH类Tau蛋白抑制剂的分子设计[J].高等学校化学学报,2012,33:2263.
[22]左柯,杜文义,代田洋,等.肺炎克雷伯碳青霉烯酶与β-内酰胺酶抑制蛋白复合物的运动模式[J].四川大学学报:自然科学版,2017,54:585.
[23]Park E,Lee M Y,Seo C S,et al.Yongdamsagantang,a traditional herbal formula,inhibits cell growth through the suppression of proliferation and inflammation in benign prostatic hyperplasia epithelial-1cells[J].J Ethnopharmacol,2017,209:230.
[24]沈骏,郑茜茜,吴晓琴,等.油茶蒲提取物对人前列腺增生BPH-1细胞的抑制作用研究[J].现代食品科技,2015,31:6.