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Wiktoria Jedwabny, Szymon Kłossowski, Trupta Purohit, Tomasz Cierpicki, Jolanta Grembecka, Edyta Dyguda-Kazimierowicz
Development and binding affinity predictions of inhibitors targeting protein-protein interactions (PPI) still represent a major challenge in drug discovery efforts. This work reports application of a predictive non-empirical model of inhibitory activity for PPI inhibitors, exemplified here for small molecules targeting the menin-mixed lineage leukemia (MLL) interaction. Systematic ab initio analysis of menin-inhibitor complexes was performed, revealing the physical nature of these interactions. Notably, the non-empirical protein-ligand interaction energy comprising electrostatic multipole and approximate dispersion terms ( E (10)El,MTP + E Das ) produced a remarkable correlation with experimentally measured inhibitory activities and enabled accurate activity prediction for new menin-MLL inhibitors...
December 1, 2017: MedChemComm
Kiran S Toti, Shanu Jain, Antonella Ciancetta, Ramachandran Balasubramanian, Saibal Chakraborty, Ryan Surujdin, Zhen-Dan Shi, Kenneth A Jacobson
Both agonists and antagonists of the UDP-activated P2Y6receptor (P2Y6R) have been proposed for therapeutic use, in conditions such as cancer, inflammation, neurodegeneration and diabetes. Uracil nucleotides containing a South-bicyclo[3.1.0]hexane ((S)-methanocarba) ring system in place of the ribose ring were synthesized and shown to be potent P2Y6R agonists in a calcium mobilization assay. The (S)-methanocarba modification was compatible with either a 5-iodo or 4-methoxyimino group on the pyrimidine, but not with a α,β-methylene 5´-diphosphate...
October 1, 2017: MedChemComm
Renato Ferreira de Freitas, Matthieu Schapira
As the protein databank (PDB) recently passed the cap of 123 456 structures, it stands more than ever as an important resource not only to analyze structural features of specific biological systems, but also to study the prevalence of structural patterns observed in a large body of unrelated structures, that may reflect rules governing protein folding or molecular recognition. Here, we compiled a list of 11 016 unique structures of small-molecule ligands bound to proteins - 6444 of which have experimental binding affinity - representing 750 873 protein-ligand atomic interactions, and analyzed the frequency, geometry and impact of each interaction type...
October 1, 2017: MedChemComm
J A H Inkster, S Zhang, V Akurathi, A Belanger, S Dubey, T Treves, A B Packard
New chemical and radiochemical syntheses are described for the preparation of [18F]Rho6G-DEG-F, an 18F-labeled analogue of the fluoresecent dye rhodamine 6G, which has shown promise as myocardidal perfusion imaging agent. Tosylated precursors of [18F]Rho6G-DEG-F amenable to 18F-labeling were obtained either through a two-step synthesis from rhodamine 6G lactone (33% yield), or in one step from rhodamine 575 (64% yield), then purified by preparative C18 chromatography. Manual synthesis of [18F]Rho6G-DEG-F was achieved in a single radiochemical step from either the tosylate salt or the tosylate/formate double salt in DMSO under standard nucleophillic aliphatic 18F-fluorination conditions (K[18F]F/K2CO3/Kryptofix 2...
October 1, 2017: MedChemComm
Romain Duroux, Antonella Ciancetta, Philip Mannes, Jinha Yu, Shireesha Boyapati, Elizabeth Gizewski, Said Yous, Francisco Ciruela, John A Auchampach, Zhan-Guo Gao, Kenneth A Jacobson
A pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine antagonist of the A2A adenosine receptor (AR) was functionalized as amine congeners, fluorescent conjugates and a sulfonate, and the A2AAR binding modes were predicted computationally. The optimal n-butyl spacer was incorporated into the following A2AAR-selective (Ki, nM) conjugates: BODIPY630/650 derivative 11 (MRS7396, 24.6) and AlexaFluor488 derivative 12 (MRS7416, 30.3). Flow cytometry of 12 in hA2AAR-expressing HEK-293 cells displayed saturable binding (low nonspecific) and inhibition by known A2AAR antagonists...
August 1, 2017: MedChemComm
Sandeep Sundriyal, Patty B Chen, Alexandra S Lubin, Gregor A Lueg, Fengling Li, Andrew J P White, Nicholas A Malmquist, Masoud Vedadi, Artur Scherf, Matthew J Fuchter
Plasmodium falciparum HKMTs (PfHKMTs) play a key role in controlling Plasmodium gene expression and represent exciting new anti-malarial epigenetic targets. Using an inhibitor series derived from the diaminoquinazoline HKMT inhibitory chemotype, we have previously identified compounds with highly promising antimalarial activity, including irreversible asexual cycle blood stage-independent cytotoxic activity at nM concentrations, oral efficacy in in vivo models of disease, and the unprecedented ability to reactivate dormant liver stage parasites (hypnozoites)...
May 1, 2017: MedChemComm
S Shaabani, C G Neochoritis, A Twarda-Clapa, B Musielak, T A Holak, A Dömling
Using the pharmacophore-based virtual screening platform ANCHOR.QUERY, we morphed our recently described Ugi-4CR scaffold towards a β-lactam scaffold with potent p53-MDM2 antagonizing activities. 2D-HSQC and FP measurements confirm potent MDM2 binding. Molecular modeling studies are used to understand the observed SAR in the β-lactam series.
May 1, 2017: MedChemComm
Exequiel O J Porta, Sebastián N Jäger, Isabel Nocito, Galina I Lepesheva, Esteban C Serra, Babu L Tekwani, Guillermo R Labadie
A series of prenyl 1,2,3-triazoles were prepared from isoprenyl azides and different alkynes. The dipolar cycloaddition reaction provided exclusively primary azide products as regioisomeric mixtures that were separated by column chromatography and fully characterized. Most of the compounds displayed antiparasitic activity against Trypanosoma cruzi and Leishmania donovani. The most active compounds were assayed as potential TcCYP51 inhibitors.
May 1, 2017: MedChemComm
Neeraj N Patwardhan, Laura R Ganser, Gary J Kapral, Christopher S Eubanks, Janghyun Lee, Bharathwaj Sathyamoorthy, Hashim M Al-Hashimi, Amanda E Hargrove
Diversification of RNA-targeted scaffolds offers great promise in the search for selective ligands of therapeutically relevant RNA such as HIV-1 TAR. We herein report the establishment of amiloride as a novel RNA-binding scaffold along with synthetic routes for combinatorial C(5)- and C(6)-diversification. Iterative modifications at the C(5)- and C(6)- positions yielded derivative 24, which demonstrated a 100-fold increase in activity over the parent dimethylamiloride in peptide displacement assays. NMR chemical shift mapping was performed using the 2D SOFAST- [(1)H-(13)C] HMQC NMR method, which allowed for facile and rapid evaluation of binding modes for all library members...
May 1, 2017: MedChemComm
Behnam Nazari, Clarissa C Forneris, Marcus I Gibson, Kyuho Moon, Kelsey R Schramma, Mohammad R Seyedsayamdost
Glycopeptide antibiotics (GPAs) have served as potent clinical drugs and as an inspiration to chemists in various disciplines. Among known GPAs, complestatin, chloropeptin, and kistamicin are unique in that they contain an unusual indole-phenol crosslink. The mechanism of formation of this linkage is unknown, and to date, the biosynthetic gene cluster of only one GPA with an indole-phenol crosslink, that of complestatin, has been identified. Here, we report the genome sequence of the kistamicin producer Nonomuraea sp...
April 1, 2017: MedChemComm
Klaas Verschueren, Mathias Cobbaut, Joachim Demaerel, Lina Saadah, Arnout R D Voet, Johan Van Lint, Wim M De Borggraeve
In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP...
March 1, 2017: MedChemComm
Rachel E Davis, Zheng Zhang, Brian S J Blagg
Inhibition of the Hsp90 C-terminus is an attractive therapeutic paradigm for the treatment of cancer, however the developmental space of C-terminal inhibitors is limited. It was hypothesized that the combination of two previously identified scaffolds into a single structure could provide a platform for which to probe the three-dimensional space within the Hsp90 C-terminal binding pocket. The resulting chimeric compounds displayed anti-proliferative activity at low micromolar concentrations and manifested inhibitory activity in an Hsp90-dependent rematuration assay...
March 1, 2017: MedChemComm
Jing Zhang, Kun Qian, Chunli Yan, Maomao He, Brenson A Jassim, Ivaylo Ivanov, Yujun George Zheng
Protein arginine methyltransferase 1 (PRMT1) is a key player for the dynamic regulation of arginine methylation. Its dysregulation and aberrant expression are implicated in various pathological conditions, and a plethora of evidence suggests that PRMT1 inhibition is of significant therapeutic value. Herein, we reported the modification of a series of diamidine compounds with varied lengths in the middle alkyl linker for PRMT1 inhibition. Decamidine (2j), which possesses the longest linker in the series, displayed 2- and 4- fold increase in PRMT1 inhibition (IC50 = 13 μM), as compared with furamdine and stilbamidine...
February 1, 2017: MedChemComm
Amandeep Singh, Nisha, Trpta Bains, Hye Jee Hahn, Nicole Liu, Christina Tam, Luisa W Cheng, Jong Kim, Anjan Debnath, Kirkwood M Land, Vipan Kumar
A series of N -alkyl tethered C-5 functionalized bis-isatins were synthesized and evaluated for antimicrobial activity against pathogenic microorganisms. The preliminary evaluation studies revealed the compound 4t , with an optimal combination of bromo-substituent at the C-5 position of isatin ring along with propyl chain linker being most active among the synthesized series exhibiting an IC 50 value of 3.72 μM against Trichomonas vaginalis while 4j exhibited an IC 50 value of 14.8 μM against Naegleria fowleri , more effective than the standard drug Miltefosine...
2017: MedChemComm
Yu Zhao, Po-Yen Liu, Kan-Yen Hsieh, Pei-Ling Hsu, Masuo Goto, Susan L Morris-Natschke, Horng-Jyh Harn, Kuo-Hsiung Lee
Z-K8 (2), the racemic form of isochaihulactone (1), previously showed significant antitumor effects in A549 and LNCaP tumor-bearing mice. In the present study, 17 derivatives of 2, were designed, synthesized and evaluated for anti-proliferative activity against four human tumor cell lines. All new derivatives exhibited high potency against A549 and P-glycoprotein (P-gp)-overexpressing KBvin. One of our new derivative exhibited greater activity against three tested tumor cells (A549, KB, and KB-VIN) than 2, and induced cell cycle arrest in the G2/M phase...
2017: MedChemComm
Kerem M Senses, Mehdi Ghasemi, Muhammad W Akbar, Murat Isbilen, Anna L Fallacara, Shoshana Frankenburg, Silvia Schenone, Michal Lotem, Maurizio Botta, Ali O Gure
Transcriptomic phenotypes defined for melanoma have been reported to correlate with sensitivity to various drugs. In this study, we aimed to define a minimal signature that could be used to distinguish melanoma sub-types in vitro, and to determine suitable drugs by which these sub-types can be targeted. By using primary melanoma cell lines, as well as commercially available melanoma cell lines, we find that the evaluation of MLANA and INHBA expression is as capable as one based on a combined analysis performed with genes for stemness, EMT and invasion/proliferation, in identifying melanoma subtypes that differ in their sensitivity to molecularly targeted drugs...
January 1, 2017: MedChemComm
Victor Goncalves, James A Brannigan, Alice Laporte, Andrew S Bell, Shirley M Roberts, Anthony J Wilkinson, Robin J Leatherbarrow, Edward W Tate
The parasite Plasmodium vivax is the most widely distributed cause of recurring malaria. N-Myristoyltransferase (NMT), an enzyme that catalyses the covalent attachment of myristate to the N-terminal glycine of substrate proteins, has been described as a potential target for the treatment of this disease. Herein, we report the synthesis and the structure-guided optimization of a series of quinolines with balanced activity against both Plasmodium vivax and Plasmodium falciparum N-myristoyltransferase (NMT).
January 1, 2017: MedChemComm
Ákos Urai, András Váradi, Levente Szőcs, Balázs Komjáti, Valerie Le Rouzic, Amanda Hunkele, Gavril W Pasternak, Susruta Majumdar, Sándor Hosztafi
It was previously reported that 6β-aminomorphinan derivatives show high affinity for opiate receptors. Novel 6β-heteroarylamidomorphinanes were designed based on the MOR selective antagonist NAP. The 6β-aminomorphinanes were prepared with stereoselective Mitsunobu reaction and subsequently acylated with nicotinic acid and isonicotinic acid chloride hydrochlorides. The receptor binding and efficacy were determined in vitro and the analgesic activity was studied in vivo. The in vitro studies revealed moderate selectivity for MOR...
January 1, 2017: MedChemComm
Moses Moustakim, Peter G K Clark, Duncan A Hay, Darren J Dixon, Paul E Brennan
In the last five years, the development of inhibitors of bromodomains has emerged as an area of intensive worldwide research. Emerging evidence has implicated a number of non-BET bromodomains in the onset and progression of diseases such as cancer, HIV infection and inflammation. The development and use of small molecule chemical probes has been fundamental to pre-clinical evaluation of bromodomains as targets. Recent efforts are described highlighting the development of potent, selective and cell active non-BET bromodomain inhibitors and their therapeutic potential...
December 7, 2016: MedChemComm
Christine A Herdman, Tracy E Strecker, Rajendra P Tanpure, Zhi Chen, Alex Winters, Jeni Gerberich, Li Liu, Ernest Hamel, Ralph P Mason, David J Chaplin, Mary Lynn Trawick, Kevin G Pinney
The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs)...
December 1, 2016: MedChemComm
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