Drug designing : open access最新文献

{"title":"Synthesis, Biological Evaluation and Modeling Studies of New Pyrido[3,4-<i>b</i>]indole Derivatives as Broad-Spectrum Potent Anticancer Agents.","authors":"Shivaputra A Patil,&nbsp;James K Addo,&nbsp;Hemantkumar Deokar,&nbsp;Shan Sun,&nbsp;Jin Wang,&nbsp;Wei Li,&nbsp;D Parker Suttle,&nbsp;Wei Wang,&nbsp;Ruiwen Zhang,&nbsp;John K Buolamwini","doi":"10.4172/2169-0138.1000143","DOIUrl":"https://doi.org/10.4172/2169-0138.1000143","url":null,"abstract":"<p><strong>Objective: </strong>There is an urgent need drugs against particularly difficult to treat solid tumors such as pancreatic, triple negative breast, lung, colon, metastatic prostate cancers and melanoma. Thus, the objective of this study was to synthesize compounds based computational modeling that indicated the pyrido[3,4-<i>b</i>]indole class bind to MDM2, a new cancer target for which there are still no drug on the market.</p><p><strong>Methods: </strong>Compounds were synthesized by established methods and tested for antiproliferative activity against a broad range of human cancer cell lines, comprising HCT116 colon, HPAC, MIA PaCa-2 and Panc-1 pancreatic, MCF-7 and MDA-MB-468 breast, A375 and WM164 melanoma, A549 lung, and LNCaP, DU145 and PC3 prostate cancer lines. Computational docking was also undertaken.</p><p><strong>Results: </strong>The novel pyrido[3,4-<i>b</i>]indoles synthesized exhibited a clear SAR with regards to antiproliferative activity, with potent broad-spectrum anticancer activity with IC₅₀s down to 80, 130, 130 and 200 nM for breast, colon, melanoma and pancreatic cancer cells, respectively. 1-Naphthyl at C1 combined with methoxy at C6 provided the best antiproliferative activity. Thus, compound <b>11</b> (1-naphthyl-6-methoxy-9<i>H</i>-pyrido[3,4-b]indole) showed the highest potency. A mechanistic feature of the compounds as a group is a strongly selective G2/M cell cycle phase arrest. Docking at on MDM2 suggested a hydrogen bond interaction between the 6-methoxy Tyr106, hydrophobic interaction with Val93, pi-pi stacking interactions with Tyr100 and His96 and hydrophobic interactions with Leu54 and Ile99. An N9-methyl group disrupted binding interactions, such as H-bond interactions involving the N9 hydrogen.</p><p><strong>Conclusion: </strong>We have identified a novel series of pyrido[3,4-<i>b</i>]indoles with potent broad spectrum anticancer activity towards the most aggressive and difficult to treat cancers including metastatic pancreatic cancer, non-small cell lung cancer, triple negative breast cancers, and BRAF^V600E mutant melanoma, as well as metastatic colon and prostate cancers. There was also evidence of selectivity towards cancer cells relative to normal cells. These compounds will serve as new leads from which novel therapeutics and molecular tools can be developed for a wide variety of cancers.</p>","PeriodicalId":72842,"journal":{"name":"Drug designing : open access","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/2169-0138.1000143","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9620111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homology Modeling of Human Concentrative Nucleoside Transporters (hCNTs) and Validation by Virtual Screening and Experimental Testing to Identify Novel hCNT1 Inhibitors.","authors":"Hemant Kumar Deokar,&nbsp;Hilaire Playa Barch,&nbsp;John K Buolamwini","doi":"10.4172/2169-0138.1000146","DOIUrl":"https://doi.org/10.4172/2169-0138.1000146","url":null,"abstract":"<p><strong>Objective: </strong>The nucleoside transporter family is an emerging target for cancer, viral and cardiovascular diseases. Due to the difficulty in the expression, isolation and crystallization of membrane proteins, there is a lack of structural information on any of the mammalian and for that matter the human proteins. Thus the objective of this study was to build homology models for the three cloned concentrative nucleoside transporters hCNT1, hCNT2 and hCNT3 and validate them for screening towards the discovery of much needed inhibitors and probes.</p><p><strong>Methods: </strong>The recently reported crystal structure of the <i>Vibrio cholerae</i> concentrative nucleoside transporter (vcCNT), has satisfactory similarity to the human CNT orthologues and was thus used as a template to build homology models of all three hCNTs. The Schrödinger modeling suite was used for the exercise. External validation of the homology models was carried out by docking a set of recently reported known hCNT1 nucleoside class inhibitors at the putative binding site using induced fit docking (IDF) methodology with the Glide docking program. Then, the hCNT1 homology model was subsequently used to conduct a virtual screening of a 360,000 compound library, and 172 compounds were obtained and biologically evaluated for hCNT 1, 2 and 3 inhibitory potency and selectivity.</p><p><strong>Results: </strong>Good quality homology models were obtained for all three hCNTs as indicated by interrogation for various structural parameters and also external validated by docking of known inhibitors. The IDF docking results showed good correlations between IDF scores and inhibitory activities; particularly for hCNT1. From the top 0.1% of compounds ranked by virtual screening with the hCNT1 homology model, 172 compounds selected and tested for against hCNT1, hCNT2 and hCNT3, yielded 14 new inhibitors (hits) of (i.e., 8% success rate). The most active compound exhibited an IC₅₀ of 9.05 μM, which shows a greater than 25-fold higher potency than phlorizin the standard CNT inhibitor (IC₅₀ of 250 μM).</p><p><strong>Conclusion: </strong>We successfully undertook homology modeling and validation for all human concentrative nucleoside transporters (hCNT 1, 2 and 3). The proof-of-concept that these models are promising for virtual screening to identify potent and selective inhibitors was also obtained using the hCNT1 model. Thus we identified a novel potent hCNT1 inhibitor that is more potent and more selective than the standard inhibitor phlorizin. The other hCNT1 hits also mostly exhibited selectivity. These homology models should be useful for virtual screening to identify novel hCNT inhibitors, as well as for optimization of hCNT inhibitors.</p>","PeriodicalId":72842,"journal":{"name":"Drug designing : open access","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/2169-0138.1000146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35632694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}