Read by QxMD icon Read

Fragment Based Lead Discovery

Lidia Araújo-Bazán, Laura B Ruiz-Avila, David Andreu, Sonia Huecas, José M Andreu
Cell division protein FtsZ is the organizer of the cytokinetic ring in almost all bacteria and a target for the discovery of new antibacterial agents that are needed to counter widespread antibiotic resistance. Bacterial cytological profiling, using quantitative microscopy, is a powerful approach for identifying the mechanism of action of antibacterial molecules affecting different cellular pathways. We have determined the cytological profile on Bacillus subtilis cells of a selection of small molecule inhibitors targeting FtsZ on different binding sites...
2016: Frontiers in Microbiology
Fatiha Benmansour, Iuni Trist, Bruno Coutard, Etienne Decroly, Gilles Querat, Andrea Brancale, Karine Barral
With the aim to help drug discovery against dengue virus (DENV), a fragment-based drug design approach was applied to identify ligands targeting a main component of DENV replication complex: the NS5 AdoMet-dependent mRNA methyltransferase (MTase) domain, playing an essential role in the RNA capping process. Herein, we describe the identification of new inhibitors developed using fragment-based, structure-guided linking and optimization techniques. Thermal-shift assay followed by a fragment-based X-ray crystallographic screening lead to the identification of three fragment hits binding DENV MTase...
October 5, 2016: European Journal of Medicinal Chemistry
Ren-Yu Qu, Jing-Fang Yang, Yu-Chao Liu, Qiong Chen, Ge-Fei Hao, Cong-Wei Niu, Zhen Xi, Guang-Fu Yang
BACKGOUND: Acetohydroxyacid synthase (AHAS; EC is the first common enzyme in the biosynthetic pathway leading to the branched-chain amino acids in plants and a wide range of microorganisms. With the long-term and wide application of AHAS inhibitors, weed resistance is becoming a global problem, which leads to an urgent demand for novel inhibitors to antagonize both wild-type and resistant AHAS. RESULTS: Pyrimidinyl-Salicylic acid derivatives, as one of the main classes of commercial AHAS herbicides, show potential anti-resistant bioactivity to wild-type and P197L mutant...
October 17, 2016: Pest Management Science
Christopher N Johnson, Daniel A Erlanson, Christopher W Murray, David C Rees
Fragment-based drug discovery (FBDD) is now well-established as a technology for generating new chemical leads and drugs. This Miniperspective provides a tabulated overview of the fragment-to-lead literature published in the year 2015, together with a commentary on trends observed across the FBDD field during this time. It is hoped that this tabulated summary will provide a useful point of reference for both FBDD practitioners and the wider medicinal chemistry community.
October 14, 2016: Journal of Medicinal Chemistry
Vladimiras Oleinikovas, Giorgio Saladino, Benjamin P Cossins, Francesco L Gervasio
Cryptic pockets, i.e. sites on protein targets that only become apparent when drugs bind, provide a promising alternative to classical binding sites for drug development. Here we investigate the nature and dynamical properties of cryptic sites in four pharmacologically relevant targets, while comparing the efficacy of various simulation-based approaches in discovering them. We find that the studied cryptic sites do not correspond to local minima in the computed conformational free energy landscape of the unliganded proteins...
October 11, 2016: Journal of the American Chemical Society
Jamil Al-Asri, Gyöngyi Gyémánt, Erika Fazekas, Gábor Lehoczki, Matthias F Melzig, Gerhard Wolber, Jérémie Mortier
Better control of postprandial hyperglycemia can be achieved by delaying the absorption of glucose resulting from carbohydrate digestion. Because α-amylase initiates the hydrolysis of polysaccharides, the design of α-amylase inhibitors can lead to the development of new treatments for metabolic disorders such as type II diabetes and obesity. In this study, a rational computer-aided approach was developed to identify novel α-amylase inhibitors. Three-dimensional pharmacophores were developed based on the binding mode analysis of six different families of compounds that bind to this enzyme...
October 11, 2016: ChemMedChem
Michiko Tawada, Shinkichi Suzuki, Yasuhiro Imaeda, Hideyuki Oki, Gyorgy Snell, Craig A Behnke, Mitsuyo Kondo, Naoki Tarui, Toshimasa Tanaka, Takanobu Kuroita, Masaki Tomimoto
A novel approach was conducted for fragment-based lead discovery and applied to renin inhibitors. The biochemical screening of a fragment library against renin provided the hit fragment which showed a characteristic interaction pattern with the target protein. The hit fragment bound only to the S1, S3, and S3(SP) (S3 subpocket) sites without any interactions with the catalytic aspartate residues (Asp32 and Asp215 (pepsin numbering)). Prior to making chemical modifications to the hit fragment, we first identified its essential binding sites by utilizing the hit fragment's substructures...
September 28, 2016: Bioorganic & Medicinal Chemistry
Volodimir Olexiouk, Gerben Menschaert
The identification of small proteins and peptides has consistently proven to be challenging. However, technological advances as well as multi-omics endeavors facilitate the identification of novel small coding sequences, leading to new insights. Specifically, the application of next generation sequencing technologies (NGS), providing accurate and sample specific transcriptome / translatome information, into the proteomics field led to more comprehensive results and new discoveries. This book chapter focuses on the inclusion of RNA-Seq and RIBO-Seq also known as ribosome profiling, an RNA-Seq based technique sequencing the +/- 30 bp long fragments captured by translating ribosomes...
2016: Advances in Experimental Medicine and Biology
Yikai Wang, Jean-Yves Wach, Patrick Sheehan, Cheng Zhong, Chenyang Zhan, Richard Harris, Steven C Almo, Joshua Bishop, Stephen J Haggarty, Alexander Ramek, Kayla N Berry, Conor O'Herin, Angela N Koehler, Alvin W Hung, Damian W Young
Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow the systematic synthesis of related fragment analogues to explore fragment-level structure-activity relationship, and finally lead to the synthesis of a more potent compound.
September 8, 2016: ACS Medicinal Chemistry Letters
Disha Patel, Janet Antwi, Pratibha C Koneru, Erik Serrao, Stefano Forli, Jacques J Kessl, Lei Feng, Nanjie Deng, Ronald M Levy, James R Fuchs, Arthur J Olson, Alan N Engelman, Joseph D Bauman, Mamuka Kvaratskhelia, Eddy Arnold
HIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors...
September 19, 2016: Journal of Biological Chemistry
Zheng Li, Jianyong Yang, Xuekun Wang, Huilan Li, Chunxia Liu, Nasi Wang, Wenlong Huang, Hai Qian
The free fatty acid receptor 1 (FFA1/GPR40) is a novel antidiabetic target based on particular mechanism in enhancing glucose-stimulated insulin secretion. Most of reported FFA1 agonists, however, have been suffered from relatively high lipophilicity and molecular weight. Aiming to develop potent agonists with improved physicochemical property, 25 compounds containing triazole scaffold and various carboxylic acid fragments were synthesized via the click chemistry. Among them, the optimal lead compound 26 with relatively low lipophicity (LogD7...
November 1, 2016: Bioorganic & Medicinal Chemistry
Angelo M Reggiani, Elena Simoni, Roberta Caporaso, Johann Meunier, Emeline Keller, Tangui Maurice, Anna Minarini, Michela Rosini, Andrea Cavalli
Alzheimer's disease (AD) is a chronic pathological condition that leads to neurodegeneration, loss of intellectual abilities, including cognition and memory, and ultimately to death. It is widely recognized that AD is a multifactorial disease, where different pathological cascades (mainly amyloid and tau) contribute to neural death and to the clinical outcome related to the disease. The currently available drugs for AD were developed according to the one-target, one-drug paradigm. In recent times, multi-target strategies have begun to play an increasingly central role in the discovery of more efficacious candidates for complex neurological conditions, including AD...
2016: Scientific Reports
David G Twigg, Noriyasu Kondo, Sophie L Mitchell, Warren R J D Galloway, Hannah F Sore, Andrew Madin, David R Spring
Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp(2) -rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp(3) character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters...
September 26, 2016: Angewandte Chemie
Chun-Feng Chang, Wen-Hsing Lin, Yi-Yu Ke, Yih-Shyan Lin, Wen-Chieh Wang, Chun-Hwa Chen, Po-Chu Kuo, John T A Hsu, Biing-Jiun Uang, Hsing-Pang Hsieh
Aurora kinases have emerged as important anticancer targets so that there are several inhibitors have advanced into clinical study. Herein, we identified novel indazole derivatives as potent Aurora kinases inhibitors by utilizing in silico fragment-based approach and knowledge-based drug design. After intensive hit-to-lead optimization, compounds 17 (dual Aurora A and B), 21 (Aurora B selective) and 30 (Aurora A selective) possessed indazole privileged scaffold with different substituents, which provide sub-type kinase selectivity...
August 16, 2016: European Journal of Medicinal Chemistry
Chao Chen, Hugh Zhu, Frédéric Stauffer, Giorgio Caravatti, Susanne Vollmer, Rainer Machauer, Philipp Holzer, Henrik Möbitz, Clemens Scheufler, Martin Klumpp, Ralph Tiedt, Kim S Beyer, Keith Calkins, Daniel Guthy, Michael Kiffe, Jeff Zhang, Christoph Gaul
Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode...
August 11, 2016: ACS Medicinal Chemistry Letters
Shin-Chen Hou, Hong-Sen Chen, Hung-Wei Lin, Wei-Ting Chao, Yao-Sheng Chen, Chi-Yu Fu, Chung-Ming Yu, Kai-Fa Huang, Andrew H-J Wang, An-Suei Yang
Immunotoxins are an important class of antibody-based therapeutics. The potency of the immunotoxins depends on the antibody fragments as the guiding modules targeting designated molecules on cell surfaces. Phage-displayed synthetic antibody scFv libraries provide abundant antibody fragment candidates as targeting modules for the immunoconjugates, but the discovery of optimally functional immunoconjugates is limited by the scFv-payload conjugation procedure. In this work, cytotoxicity screening of non-covalently assembled immunotoxins was developed in high throughput format to discover highly functional synthetic antibody fragments for delivering toxin payloads...
2016: Scientific Reports
Nathaniel G Mahieu, Jonathan L Spalding, Susan J Gelman, Gary J Patti
Analysis of a single analyte by mass spectrometry can result in the detection of more than 100 degenerate peaks. These degenerate peaks complicate spectral interpretation and are challenging to annotate. In mass spectrometry-based metabolomics, this degeneracy leads to inflated false discovery rates, data sets containing an order of magnitude more features than analytes, and an inefficient use of resources during data analysis. Although software has been introduced to annotate spectral degeneracy, current approaches are unable to represent several important classes of peak relationships...
September 20, 2016: Analytical Chemistry
Sunandini Sharma, Kritika Karri, Ishwor Thapa, Dhundy Bastola, Dario Ghersi
BACKGROUND: Fragment-based approaches have now become an important component of the drug discovery process. At the same time, pharmaceutical chemists are more often turning to the natural world and its extremely large and diverse collection of natural compounds to discover new leads that can potentially be turned into drugs. In this study we introduce and discuss a computational pipeline to automatically extract statistically overrepresented chemical fragments in therapeutic classes, and search for similar fragments in a large database of natural products...
2016: BMC Medical Genomics
Qingwen Zhang, Xuejin Zhang, Qidong You
The success of the first approved kinase inhibitor imatinib has spurred great interest in the development of type II inhibitors targeting the inactive DFG-out conformation, wherein the Phe of the DFG motif at the start of the activation loop points into the ATP binding site. Nevertheless, kinase inhibitors launched so far are heavily biased toward type I inhibitors targeting the active DFG-in conformation, wherein the Phe of the DFG motif flips by approximately 180° relative to the inactive conformation, resulting in Phe and Asp swapping their positions...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Rongsheng Ma, Pengchao Wang, Jihui Wu, Ke Ruan
Fragment-based lead discovery (FBLD) has proven fruitful during the past two decades for a variety of targets, even challenging protein-protein interaction (PPI) systems. Nuclear magnetic resonance (NMR) spectroscopy plays a vital role, from initial fragment-based screening to lead generation, because of its power to probe the intrinsically weak interactions between targets and low-molecular-weight fragments. Here, we review the NMR FBLD process from initial library construction to lead generation. We describe technical aspects regarding fragment library design, ligand- and protein-observed screening, and protein-ligand structure model generation...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"