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Fragment Based Lead Discovery

Bas Lamoree, Roderick E Hubbard
Fragment-based lead discovery has emerged over the past two decades as a successful approach to generate novel lead candidates in drug discovery programs. The two main advantages over conventional high-throughput screening (HTS) are more efficient sampling of chemical space and tighter control over the physicochemical properties of the lead candidates. Antibiotics are a class of drugs with particularly strict property requirements for efficacy and safety. The development of novel antibiotics has slowed down so much that resistance has now evolved against every available antibiotic drug...
July 2018: SLAS Discovery
Feng Wang, Kyu Ok Jeon, James M Salovich, Jonathan D Macdonald, Joseph Alvarado, Rocco D Gogliotti, Jason Phan, Edward T Olejniczak, Qi Sun, Shidong Wang, DeMarco V Camper, Joannes P Yuh, J Grace Shaw, Jiqing Sai, Olivia W Rossanese, William P Tansey, Shaun R Stauffer, Stephen W Fesik
WDR5 is a chromatin regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed lineage leukemia. Here we describe the discovery of potent and selective WDR5 WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN-site within WDR5. Members of a 6,7-dihydro-5 H-pyrrolo[1,2- a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants < 10 nM and micromolar cellular activity against an AML leukemia cell line...
June 11, 2018: Journal of Medicinal Chemistry
Laurent Hoffer, Yuliia Valerievna Voitovich, Brigitt Raux, Kendall Carrasco, Christophe Muller, Aleksey Yurievich Fedorov, Carine Derviaux, Agnes Amouric, Stephane Betzi, Dragos Horvath, Alexandre Varnek, Yves Collette, Sébastien Combes, Philippe Roche, Xavier Morelli
Over the past few decades, hit identification has been greatly facilitated by advances in high-throughput and fragment-based screenings. One major hurdle remaining in drug discovery is process automation of hit-to-lead (H2L) optimization. Here, we report a time and cost-efficient integrated strategy for H2L optimization and partially automated design of potent chemical probes consisting of focused chemical library design and virtual screening coupled with robotic diversity-oriented de novo synthesis and automated in vitro evaluation...
June 8, 2018: Journal of Medicinal Chemistry
Melanie Leveridge, Chun-Wa Chung, Jeffrey W Gross, Christopher B Phelps, Darren Green
There has been much debate around the success rates of various screening strategies to identify starting points for drug discovery. Although high-throughput target-based and phenotypic screening has been the focus of this debate, techniques such as fragment screening, virtual screening, and DNA-encoded library screening are also increasingly reported as a source of new chemical equity. Here, we provide examples in which integration of more than one screening approach has improved the campaign outcome and discuss how strengths and weaknesses of various methods can be used to build a complementary toolbox of approaches, giving researchers the greatest probability of successfully identifying leads...
June 1, 2018: SLAS Discovery
Mathilde Lescanne, Puneet Ahuja, Anneloes Blok, Monika Timmer, Tomas Akerud, Marcellus Ubbink
Liquid-state NMR spectroscopy is a powerful technique to elucidate binding properties of ligands on proteins. Ligands binding in hydrophobic pockets are often in close proximity to methyl groups and binding can lead to subtle displacements of methyl containing side chains to accommodate the ligand. To establish whether pseudocontact shifts can be used to characterize ligand binding and the effects on methyl groups, the N-terminal domain of HSP90 was tagged with caged lanthanoid NMR probe 5 at three positions and titrated with a ligand...
June 2, 2018: Journal of Biomolecular NMR
Agni F M Gavriilidou, Finn P Holding, Joseph E Coyle, Renato Zenobi
Native electrospray ionization mass spectrometry (ESI-MS) was applied to analyze the binding of compounds generated during fragment-based drug discovery (FBDD) campaigns against two functionally distinct proteins, the X-linked inhibitor of apoptosis protein (XIAP) and cyclin-dependent kinase 2 (CDK2). Compounds of different molecular weights and a wide range of binding affinities obtained from the hits to leads and lead optimization stages of FBDD campaigns were studied, and their dissociation constants (Kd ) were measured by native ESI-MS...
May 1, 2018: SLAS Discovery
Siew Pheng Lim, Christian G Noble, Shahul Nilar, Pei-Yong Shi, Fumiaki Yokokawa
Flavivirus NS5 RNA-dependent RNA polymerase (RdRp) is an important drug target. Whilst a number of allosteric inhibitors have been described for Hepatitis C virus RdRp, few have been described for DENV RdRp. In addition, compound screening campaigns have not yielded suitable leads for this enzyme. Using fragment-based screening via X-ray crystallography, we identified a biphenyl acetic acid fragment that binds to a novel pocket of the dengue virus (DENV) RdRp, in the thumb/palm interface, close to its active site (termed "N pocket")...
2018: Advances in Experimental Medicine and Biology
Jun Shang, Ben Hu, Junmei Wang, Feng Zhu, Yu Kang, Dan Li, Huiyong Sun, De-Xin Kong, Tingjun Hou
This is a new golden age for the drug discovery based on natural products derived from both marine and terrestrial sources. Herein, a straightforward but important question is what are the major structural differences between marine natural products (MNPs) and terrestrial natural products (TNPs). To answer this question, we analyzed the important physicochemical properties, structural features and drug-likeness of the two types of natural products and discussed their differences from the perceptive of evolution...
May 24, 2018: Journal of Chemical Information and Modeling
Tom D Heightman, Valerio Berdini, Hannah Braithwaite, Ildiko Maria Buck, Megan Cassidy, Juan Castro, Aurelie Courtin, James E H Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M Griffiths-Jones, John F Lyons, Vanessa Martins, Sandra Muench, Joanne M Munck, David Norton, Marc O'Reilly, Nick Palmer, Puja Pathuri, Michael Reader, David C Rees, Sharna J Rich, Caroline Richardson, Harpreet Saini, Neil T Thompson, Nicola G Wallis, Hugh Walton, Nicola E Wilsher, Alison J-A Woolford, Michael Cooke, David Cousin, Stuart Onions, Jonathan Shannon, John Watts, Christopher W Murray
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity...
May 18, 2018: Journal of Medicinal Chemistry
Nicola Luise, Paul Wyatt
Synthesising polar semi-saturated bicyclic heterocycles can lead to better starting points for fragment-based drug discovery (FBDD) programs. This communication highlights the application of diverse chemistry to construct bicyclic systems from a common intermediate, where pyrazole, a privileged heteroaromatic able to bind effectively to biological targets, is fused to diverse saturated counterparts. The generated fragments can be further developed either after confirmation of their binding pose or early in the process, as their synthetic intermediates...
May 7, 2018: Chemistry: a European Journal
Yann Ayotte, François Bilodeau, Albert Descoteaux, Steven R LaPlante
A rapid and practical approach for the discovery of new chemical matter for targeting pathogens and diseases is described. Fragment-based phenotypic lead discovery (FPLD) combines aspects of traditional fragment-based lead discovery (FBLD), which involves the screening of small-molecule fragment libraries to target specific proteins, with phenotypic lead discovery (PLD), which typically involves the screening of drug-like compounds in cell-based assays. To enable FPLD, a diverse library of fragments was first designed, assembled, and curated...
May 2, 2018: ChemMedChem
Shashank P Katiyar, Vidhi Malik, Anjani Kumari, Kamya Singh, Durai Sundar
Fragment-based drug design strategies have been used in drug discovery since it was first demonstrated using experimental structural biology techniques such as nuclear magnetic resonance (NMR) and X-ray crystallography. The underlying idea is that existing or new chemical entities with known desirable properties may serve both as tool compounds and as starting points for hit-to-lead expansion. Despite the recent advancements, there remain challenges to overcome, such as assembly of the synthetically feasible structures, development of scoring functions to correlate structure and their activities, and fine tuning of the promising molecules...
2018: Methods in Molecular Biology
Colin K Skepper, Robert J Moreau, Brent A Appleton, Bret M Benton, Joseph E Drumm, Brian Y Feng, Mei Geng, Cheng Hu, Cindy Li, Andreas Lingel, Yipin Lu, Mulugeta Mamo, Wosenu Mergo, Mina Mostafavi, Christopher M Rath, Micah Steffek, Kenneth T Takeoka, Kyoko Uehara, Lisha Wang, Jun-Rong Wei, Lili Xie, Wenjian Xu, Qiong Zhang, Javier de Vicente
In the preceding manuscript [ Moreau et al. 2018 , 10.1021/acs.jmedchem.7b01691 ] we described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified: triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4-5 orders of magnitude greater than their respective fragment starting points...
April 26, 2018: Journal of Medicinal Chemistry
Agnieszka Zagorska, Anna Partyka, Adam Bucki, Alicja Gawalska, Anna Czopek, Maciej Pawlowski
BACKGROUND: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases. OBJECTIVE: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery...
March 8, 2018: Current Medicinal Chemistry
Long Chen, Chunlin Zhuang, Junjie Lu, Yan Jiang, Chunquan Sheng
Targeting KRAS-PDEδ protein-protein interactions with small molecules represents a promising opportunity for developing novel antitumor agents. However, current KRAS-PDEδ inhibitors are limited by poor cellular antitumor potency and the druggability of the target remains to be validated by new inhibitors. To tackle these challenges, herein, novel, highly potent KRAS-PDEδ inhibitors were identified by fragment-based drug design, providing promising lead compounds or chemical probes for investigating the biological functions and druggability of KRAS-PDEδ interaction...
March 22, 2018: Journal of Medicinal Chemistry
György Szabó, György I Túrós, Sándor Kolok, Mónika Vastag, Zsuzsanna Sánta, Miklós Dékány, György I Lévay, István Greiner, Minami Natsumi, Watanabe Tatsuya, György M Keserű
Metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators (PAMs) have been implicated as potential pharmacotherapy for psychiatric conditions. Screening our corporate compound deck, we identified a benzotriazole fragment (4) that was rapidly optimized to a potent and metabolically stable early lead (16). The highly lipophilic character of 16, together with its limited solubility, permeability, and high protein binding, however, did not allow reaching of the proof of concept in vivo. Since further attempts on the optimization of druglike properties were unsuccessful, the original hit 4 has been revisited and was optimized following the principles of fragment based drug discovery (FBDD)...
March 14, 2018: Journal of Medicinal Chemistry
Robert J Moreau, Colin K Skepper, Brent A Appleton, Anke Blechschmidt, Carl J Balibar, Bret M Benton, Joseph E Drumm, Brian Y Feng, Mei Geng, Cindy Li, Mika K Lindvall, Andreas Lingel, Yipin Lu, Mulugeta Mamo, Wosenu Mergo, Valery Polyakov, Thomas M Smith, Kenneth Takeoka, Kyoko Uehara, Lisha Wang, Jun-Rong Wei, Andrew H Weiss, Lili Xie, Wenjian Xu, Qiong Zhang, Javier de Vicente
The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria...
April 26, 2018: Journal of Medicinal Chemistry
Shengjun Fu, Quandeng Nie, Yuying Ma, Ping Song, Xuejiao Ren, Cheng Luo, Luqing Shang, Zheng Yin
Target-guided screening of fragments (TGSOF) was developed and employed in the identification of EV-A71 3C protease (3Cpro ) inhibitors. We identified 4-acetylpyridine and 3-acetylpyridine as effective P3 fragments of an inhibitor and obtained the corresponding irreversible inhibitors 12c and 12fvia this method. Furthermore, based on 12c and 12f, we have obtained reversible inhibitors 17c and 17f. These results demonstrated that TGSOF is a useful strategy for identifying suitable fragments in developing leads in drug discovery...
March 15, 2018: Chemical Communications: Chem Comm
Gerard Martinez-Rosell, Matt J Harvey, Gianni De Fabritiis
Fragment-based drug discovery (FBDD) has become a mainstream approach in drug design because it allows the reduction of the chemical space and screening libraries while identifying fragments with high protein-ligand efficiency interactions that can later be grown into drug-like leads. In this work, we leverage high-throughput molecular dynamics (MD) simulations to screen a library of 129 fragments for a total of 5.85 ms against the CXCL12 monomer, a chemokine involved in inflammation and diseases such as cancer...
March 26, 2018: Journal of Chemical Information and Modeling
Qiuping Xiang, Chao Wang, Yan Zhang, Xiaoqian Xue, Ming Song, Cheng Zhang, Chenchang Li, Chun Wu, Kuai Li, Xiaoyan Hui, Yulai Zhou, Jeff B Smaill, Adam V Patterson, Donghai Wu, Ke Ding, Yong Xu
The CREB (cAMP responsive element binding protein) binding protein (CBP) and its homolog EP300 have emerged as new therapeutic targets for the treatment of cancer and inflammatory diseases. Here we report the identification, optimization and evaluation of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 inhibitors starting from fragment-based virtual screening (FBVS). A cocrystal structure of the inhibitor (22e) in complex with CBP provides a solid structural basis for further optimization. The most potent compound 32h binds to the CBP bromodomain and has an IC50 value of 0...
March 10, 2018: European Journal of Medicinal Chemistry
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