共查询到20条相似文献,搜索用时 15 毫秒
1.
Tanaji T. Talele Payal Arora Shridhar S. Kulkarni Maulik R. Patel Satyakam Singh Maksim Chudayeu Neerja Kaushik-Basu 《Bioorganic & medicinal chemistry》2010,18(13):4630-4638
Hepatitis C virus (HCV) NS5B polymerase is a key target for the development of therapeutic agents aimed at the treatment of HCV infections. Here we report on the identification of novel allosteric inhibitors of HCV NS5B through a combination of structure-based virtual screening, synthesis and structure–activity relationship (SAR) optimization approach. Virtual screening of 260,000 compounds from the ChemBridge database against the tetracyclic indole inhibitor binding pocket of NS5B (allosteric pocket-1, AP-1), sequentially down-sized the library by 4 orders of magnitude to yield 23 candidates. In vitro evaluation of the NS5B inhibitory activity of the in-silico selected compounds resulted in 17% hit rate, identifying two novel chemotypes. Of these, compound 3, bearing the rhodanine scaffold, proved amenable for productive SAR exploration and synthetic modification. As a result, 25 derivatives that exhibited IC50 values ranging from 7.7 to 68.0 μM were developed. Docking analysis of lead compound 28 within the tetracyclic indole- and benzylidene-binding allosteric pockets (AP-1 and AP-3, respectively) of NS5B revealed topological similarities between these two pockets. Compound 28, a novel rhodanine analog with NS5B inhibitory potency in the low micromolar level range may be a promising lead for future development of more potent NS5B inhibitors. 相似文献
2.
Cliff C. Cheng Gerald W. Shipps Zhiwei Yang Noriyuki Kawahata Charles A. Lesburg José S. Duca Jamie Bandouveres Jack D. Bracken Chuan-kui Jiang Sony Agrawal Eric Ferrari H.-C. Huang 《Bioorganic & medicinal chemistry letters》2010,20(7):2119-2124
SAR exploration from an initial hit, (S)-N-(2-cyclohexenylethyl)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)benzamide (1), identified using our proprietary automated ligand identification system (ALIS),1 has led to a novel series of selective hepatitis C virus (HCV) NS5B polymerase inhibitors with improved in vitro potency as exemplified by (S)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)-N-isopentyl-N-methylbenzamidecarboxamide (41) (IC50 = 0.5 μM). The crystal structure of an analogue (44) was solved and provided rationalization of the SAR of this series, which binds in a distinct manner in the palm domain of NS5B, consistent with biochemical analysis using enzyme mutant variants. These data warrant further lead optimization efforts on this novel series of non-nucleoside inhibitors targeting the HCV polymerase. 相似文献
3.
Kisun Ryu Nam Doo Kim Seong Il Choi Cheol Kyu Han Jeong Hyeok Yoon Kyoung Tai No Kyun-Hwan Kim Baik L. Seong 《Bioorganic & medicinal chemistry》2009,17(8):2975-2982
Hepatitis C virus (HCV) is the major etiological agent of non-A, non-B hepatitis where no effective treatment is available. The HCV NS5B with RNA-dependent RNA polymerase (RdRp) activity is a key target for the treatment of HCV infection. Here we report novel NS5B polymerase inhibitors identified by virtual screening and in vitro evaluation of their inhibitory activities. On the basis of a newly identified binding pocket of NS5B, distinct from the nucleotide binding site but highly conserved among various HCV isolates, we performed virtual screening of compounds that fit this binding pocket from the available chemical database of 3.5 million compounds. The inhibitory activities of the in silico selected 119 compounds were estimated with in vitro RdRp assay. Three compounds with IC50 values of about 20 μM were identified, and their kinetic analyses suggest that these compounds are noncompetitive inhibitors with respect to the ribonucleotide substrate. Furthermore, the single-point mutations of the conserved residues in the binding pocket of NS5B resulted in the significant decrease of the RdRp activity, indicating that the binding pocket presented here might be important for the therapeutic intervention of HCV. These novel inhibitors would be useful for the development of effective anti-HCV agents. 相似文献
4.
Tino Wilson Sanchez Bikash Debnath Frauke Christ Hiroyuki Otake Zeger Debyser Nouri Neamati 《Bioorganic & medicinal chemistry》2013,21(4):957-963
Human lens epithelium-derived growth factor (LEDGF)/p75 plays an important role in the HIV life cycle by stimulating integrase (IN)-led viral DNA integration into cellular chromosomes. Mechanistic studies show the majority of IN inhibitors chelate magnesium ions in the catalytic active site, a region topologically distant from the LEDGF/p75 binding site. Compounds disrupting the formation of LEDGF/p75 and IN complexes serve as a novel mechanistic approach different from current antiretroviral therapies. We previously built pharmacophore models mimicking LEDGF/p75 residues and identified four classes of LEDGF/p75-IN inhibitors. Substructure and similarity searches yielded additional LEDGF/p75-IN inhibitors containing an acylhydrazone moiety. The most potent of the acylhydrazones inhibited LEDGF/p75-IN interaction with an IC50 value of 400 nM. We explored structure–activity relationships (SAR) and identified new acylhydrazones, hydrazines, and diazenes as lead molecules for further optimization. Two lead LEDGF/p75-IN inhibitors showed antiviral activity. 相似文献
5.
Pierre L. Beaulieu Eric Jolicoeur James Gillard Christian Brochu René Coulombe Nathalie Dansereau Jianmin Duan Michel Garneau Araz Jakalian Peter Kühn Lisette Lagacé Steven LaPlante Ginette McKercher Stéphane Perrault Martin Poirier Marc-André Poupart Timothy Stammers Louise Thauvette Bounkham Thavonekham George Kukolj 《Bioorganic & medicinal chemistry letters》2010,20(3):857-861
SAR studies at the N1-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons (EC50 <200 nM). This class of inhibitors displayed improved physicochemical properties and favorable ADME-PK profiles over previously described analogs in this class. 相似文献
6.
Kalata B1 is a plant protein with remarkable thermal, chemical and enzymatic stability. Its potential applications could be centered on the possibility of using its cyclic structure and cystine knot motif as a scaffold for the design of stable pharmaceuticals. To discover potent dengue NS2B–NS3 protease inhibitors, we have prepared various kalata B1 analogues by varying the amino acid sequence. Mass spectrometric and biochemical investigations of these analogues revealed a cyclopeptide whose two fully oxidized forms are substrate-competitive inhibitors of the dengue viral NS2B–NS3 protease. Both oxidized forms showed potent inhibition with Ki of 1.39 ± 0.35 and 3.03 ± 0.75 μM, respectively. 相似文献
7.
《Bioorganic & medicinal chemistry》2016,24(14):3102-3107
Biological screening of a library of synthesized benzo[c]chromene-7,10-dione natural products against human farnesyltransferase (FTase) has identified tecomaquinone I (IC50 of 0.065 ± 0.004 μM) as being one of the more potent natural product inhibitors identified to date. Anti-plasmodial screening of the same library against a drug-resistant strain of Plasmodium falciparum identified the structurally-related dichromenol tectol as a moderately active growth inhibitor with an IC50 3.44 ± 0.20 μM. Two novel series of analogues, based on the benzo[c]chromene-7,10-dione scaffold, were subsequently synthesized, with one analogue exhibiting farnesyltransferase inhibitory activity in the low micromolar range. A preliminary structure–activity relationship (SAR) study has identified different structural requirements for anti-malarial activity in comparison to FTase activities for these classes of natural products. Our results identify tecomaquinone I as a novel scaffold from which more potent inhibitors of human and parasitic FTase could be developed. 相似文献
8.
Sun Jun Park Eunjin Kim Miyoun Yoo Joo-Youn Lee Chi Hoon Park Jong Yeon Hwang Jae Du Ha 《Bioorganic & medicinal chemistry letters》2017,27(18):4399-4404
A novel 6-aminopurine scaffold bearing an N9-cis-cyclobutyl moiety was designed using structure-based molecular design based on two known CDK inhibitors, dinaciclib and Cmpd-27. A series of novel 6-aminopurine compounds was prepared for structure–activity relationship (SAR) studies of CDK2 and CDK5 inhibitors. Among the compounds synthesized, compound 8l displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC50 = 2.1 and 4.8 nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines. Here, we report the synthesis and evaluation of novel 6-aminopurine derivatives and present molecular docking models of compound 81 with CDK2 and CDK5. 相似文献
9.
Pierre L. Beaulieu René Coulombe Jianmin Duan Gulrez Fazal Cédrickx Godbout Oliver Hucke Araz Jakalian Marc-André Joly Olivier Lepage Montse Llinàs-Brunet Julie Naud Martin Poirier Nathalie Rioux Bounkham Thavonekham George Kukolj Timothy A. Stammers 《Bioorganic & medicinal chemistry letters》2013,23(14):4132-4140
We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B–ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. 相似文献
10.
He Huang Jingui Ma Jianmei Shi Linghua Meng Hualiang Jiang Jian Ding Hong Liu 《Bioorganic & medicinal chemistry》2010,18(13):4615-4624
We report here the discovery of novel purine derivatives with potent and selective inhibitory activity against c-Src tyrosine kinase by adopting a strategy integrating focused combinatorial library design, virtual screening, chemical synthesis, and bioassay. Thirty two compounds were selected and synthesized. All compounds showed potent inhibitory activity against c-Src kinase with IC50 values ranging from 3.14 μM to 0.02 μM. Compound 5i was identified as one of the most potent agent with an IC50 120 times lower than those of the hits. The high hit rate (100%) and the potency of the new Src kinase inhibitors demonstrated the efficiency of the strategy for the focused library design and virtual screening. The novel active chemical entities reported here should be good leads for further development of purine-based anticancer drugs targeting Src tyrosine kinase. 相似文献
11.
David A. Ellis Julie K. Blazel Chinh V. Tran Frank Ruebsam Douglas E. Murphy Lian-Sheng Li Jingjing Zhao Yuefen Zhou Helen M. McGuire Alan X. Xiang Stephen E. Webber Qiang Zhao Qing Han Charles R. Kissinger Matthew Lardy Alberto Gobbi Richard E. Showalter Amit M. Shah Mei Tsan Rupal A. Patel Leo Kirkovsky 《Bioorganic & medicinal chemistry letters》2009,19(21):6047-6052
The discovery of 5,5′- and 6,6′-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 μM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed. 相似文献
12.
Zeder-Lutz G Choulier L Besse M Cousido-Siah A Figueras FX Didier B Jung ML Podjarny A Altschuh D 《Analytical biochemistry》2012,421(2):417-427
We investigated the suitability of surface plasmon resonance (SPR) for providing quantitative binding information from direct screening of a chemical library on protein tyrosine phosphatase 1b (PTP1B). The experimental design was established from simulations to detect binding with KD < 10?4 M. The 1120 compounds (cpds) were injected sequentially at concentrations [C(cpd)] of 0.5 or 10 μM over various target surfaces. An optimized evaluation procedure was applied. More than 90% of cpds showed no detectable signal in four screens. The 30 highest responders at C(cpd) = 10 μM, of which 25 were selected in at least one of three screens at C(cpd) = 0.5 μM, contained 22 promiscuous binders and 8 potential PTP1B-specific binders with KD ~ 10?5 M. Inhibition of PTP1B activity was assayed and confirmed for 6 of these, including sanguinarine, a known PTP1B inhibitor. C(cpd) dependence studies fully confirmed screening conclusions. The quantitative consistency of SPR data led us to propose a structure–activity relationship (SAR) model for developing selective PTP1B inhibitors based on the ranking of 10 arylbutylpiperidine analogs. 相似文献
13.
Dmitry O. Koltun Eric Q. Parkhill Natalya I. Vasilevich Andrei I. Glushkov Timur M. Zilbershtein Alexei V. Ivanov Andrew G. Cole Ian Henderson Nathan A. Zautke Sandra A. Brunn Nevena Mollova Kwan Leung Jeffrey W. Chisholm Jeff Zablocki 《Bioorganic & medicinal chemistry letters》2009,19(7):2048-2052
We identified a series of structurally novel SCD (Δ9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC50 value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Δ5 and Δ6 desaturases. 相似文献
14.
15.
Aaron M. Bender Rebecca L. Weiner Vincent B. Luscombe Sonia Ajmera Hyekyung P. Cho Sichen Chang Xiaoyan Zhan Alice L. Rodriguez Colleen M. Niswender Darren W. Engers Thomas M. Bridges P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(15):3576-3581
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s < 200 nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp = 2.1, Kp,uu = 1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists. 相似文献
16.
Bhargav A. Patel Ramalingam Krishnan Nikhil Khadtare K.R. Gurukumar Amartya Basu Payal Arora Aaditya Bhatt Maulik R. Patel Dibyendu Dana Sanjai Kumar Neerja Kaushik-Basu Tanaji T. Talele 《Bioorganic & medicinal chemistry》2013,21(11):3262-3271
Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50 = 7.7 μM) and 2 (IC50 = 10.6 μM) as represented by hybrid compound 27 (IC50 = 6.7 μM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the d-isomers 41 (IC50 = 19.3 μM) and 45 (IC50 = 5.4 μM) as enantiomers of the l-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition. 相似文献
17.
Brian W. Budzik Karen A. Evans David D. Wisnoski Jian Jin Ralph A. Rivero George R. Szewczyk Channa Jayawickreme David L. Moncol Hongshi Yu 《Bioorganic & medicinal chemistry letters》2010,20(4):1363-1367
A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent agonists of the human TGR5 G-protein-coupled receptor is described. Many analogues were readily accessible via solution-phase synthesis which resulted in the rapid identification of key structure–activity relationships (SAR), and the discovery of potent exemplars (up to pEC50 = 9). Details of the SAR and optimization of this series are presented herein. 相似文献
18.
Fengzhi Yang Fangzhou Xie Ying Zhang Yu Xia Wenlu Liu Faqin Jiang Celine Lam Yixue Qiao Dongsheng Xie Jianqi Li Lei Fu 《Bioorganic & medicinal chemistry letters》2017,27(10):2166-2170
Known PTP1B inhibitors with bis-anionic moieties exhibit potent inhibitory activity, good selectivity, however, they are incapable of penetrating cellular membranes. Based upon our finding of a new pharmacophoric group in inhibition of PTP1B and the structural characteristics of the binding pocket of PTP1B, a series of bis-arylethenesulfonic acid ester derivatives were designed and synthesized. These novel molecules, particularly Y-shaped bis-arylethenesulfonic acid ester derivatives, exhibited high PTP1B inhibitory activity, moderate selectivity, and great potential in penetrating cellular membranes (compound 7p, CLog P = 9.73, Papp = 9.6 × 10-6 cm/s; IC50 = 140, 1290 and 920 nM on PTP1B, TCPTP and SHP2, respectively). Docking simulations suggested that these Y-shaped inhibitors might interact with multiple secondary binding sites in addition to the catalytic site of PTP1B. 相似文献
19.
《Bioorganic & medicinal chemistry》2014,22(17):4968-4997
TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50 = 3.6 nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described. 相似文献
20.
Deena S. Lasheen Mohamed A.H. Ismail Dalal A. Abou El Ella Nasser S.M. Ismail Sameh Eid Susan Vleck Jeffrey S. Glenn Andrew G. Watts Khaled A.M. Abouzid 《Bioorganic & medicinal chemistry》2013,21(10):2742-2755
Two series of peptidomimetics were designed, prepared and evaluated for their anti-HCV activity. One series possesses a C-terminal carboxylate functionality. In the other series, the electrophilic vinyl sulfonate moiety was introduced as a novel class of HCV NS3/4A protease inhibitors. In vitro based studies were then performed to evaluate the efficacies of the inhibitors using Human hepatoma cells, with the vinyl sulfonate ester (10) in particular, found to have highly potent anti-HCV activity with an EC50 = 0.296 μM. Finally, molecular modeling studies were performed through docking of the synthesized compounds in the HCV NS3/4A protease active site to assess their binding modes with the enzyme and gain further insight into their structure–activity relationships. 相似文献