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Fragment Based Lead Discovery

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, 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, Cindy Li, Javier de Vicente
In the preceding manuscript 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...
March 18, 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 István Túrós, Sándor Kolok, Mónika Vastag, Zsuzsanna Sánta, Miklós Dékány, György I Lévay, István Greiner, Minami Natsumi, Watanabe Tatsuya, Gyorgy M Keseru
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 to reach 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 5, 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 is 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...
March 2, 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 2, 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 5.85ms against the CXCL12 monomer, a chemokine involved in inflammation and diseases such as cancer...
February 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 IC 50 value of 0...
February 6, 2018: European Journal of Medicinal Chemistry
Daoguang Zhang, Solomon Asnake, Jingya Zhang, Per-Erik Olsson, Guisen Zhao
Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5-methyl-1H-pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide...
February 1, 2018: Chemical Biology & Drug Design
Jaru Taechalertpaisarn, Bosheng Zhao, Xiaowen Liang, Kevin Burgess
The protein-protein interaction between proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR) is a relatively new, and extremely important, validated therapeutic target for treatment and prevention of heart disease. Experts in the area agree that the first small molecules to disrupt PCSK9·LDLR would represent a milestone in this field, yet few credible leads have been reported. This paper describes how side-chain orientations in preferred conformations of carefully designed chemotypes were compared with LDLR side chains at the PCSK9·LDLR interface to find molecules that would mimic interface regions of LDLR...
February 26, 2018: Journal of the American Chemical Society
Sten Ohlson, Minh-Dao Duong-Thi
Fragment-based drug discovery is an important tool for design of small molecule hit-to-lead compounds against various biological targets. Several approved drugs have been derived from an initial fragment screen and many such candidates are in various stages of clinical trials. Finding fragment hits, that are suitable for optimisation by medicinal chemists, is still a challenge as the binding between the small fragment and its target is weak in the range of mM to µM of Kd and irrelevant non-specific interactions are abundant in this area of transient interactions...
January 25, 2018: Methods: a Companion to Methods in Enzymology
Robert Schulz, Amira Atef, Daniel Becker, Franziska Gottschalk, Carolin Tauber, Stefan Wagner, Christoph Arkona, Atef A Abdel-Hafez, Hassan H Farag, Jörg Rademann, Gerhard Wolber
Lead structure discovery mainly focuses on the identification of noncovalently binding ligands. Covalent linkage, however, is an essential binding mechanism for a multitude of successfully marketed drugs, although discovered by serendipity in most cases. We present a concept for the design of fragments covalently binding to proteases. Covalent linkage enables fragment binding unrelated to affinity to shallow protein binding sites and at the same time allows differentiated targeted hit verification and binding location verification through mass spectrometry...
February 8, 2018: Journal of Medicinal Chemistry
C M Hayre, S Blackman, K Carlton, A Eyden
INTRODUCTION: Since the discovery of X-rays by Rontgen in 1895, lead (Pb) has been used to limit ionising radiation for both operators and patients due to its high density and high atomic number (Z = 82). This study explores the attitudes and perceptions of diagnostic radiographers applying Pb protection during general radiographic examinations, an area underexplored within a contemporary radiographic environment(s). METHODS: This paper presents findings from a wider ethnographic study undertaken in the United Kingdom (UK)...
February 2018: Radiography
Zheng Zhang, Meghan Burke, Yuri A Mirokhin, Dmitrii V Tchekhovskoi, Sanford P Markey, Wen Yu, Raghothama Chaerkady, Sonja Hess, Stephen E Stein
Spectral library searching (SLS) is an attractive alternative to sequence database searching (SDS) for peptide identification due to its speed, sensitivity, and ability to include any selected mass spectra. While decoy methods for SLS have been developed for low mass accuracy peptide spectral libraries, it is not clear that they are optimal or directly applicable to high mass accuracy spectra. Therefore, we report the development and validation of methods for high mass accuracy decoy libraries. Two types of decoy libraries were found to be suitable for this purpose...
February 2, 2018: Journal of Proteome Research
Lewis D Turner, Abbey J Summers, Laura O Johnson, Margaret A Knowles, Colin W G Fishwick
Structure-based drug design (SBDD) has become a powerful tool utilized by medicinal chemists to rationally guide the drug discovery process. Herein, we describe the use of SPROUT, a de novo -based program, to identify an indazole-based pharmacophore for the inhibition of fibroblast growth factor receptor (FGFR) kinases, which are validated targets for cancer therapy. Hit identification using SPROUT yielded 6-phenylindole as a small fragment predicted to bind to FGFR1. With the aid of docking models, several modifications to the indole were made to optimize the fragment to an indazole-containing pharmacophore, leading to a library of compounds containing 23 derivatives...
December 14, 2017: ACS Medicinal Chemistry Letters
Qiufeng Liu, Fubao Huang, Xiaojing Yuan, Kai Wang, Yi Zou, Jianhua Shen, Yechun Xu
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained...
December 28, 2017: Journal of Medicinal Chemistry
Paola Di Lello, Richard Pastor, Jeremy M Murray, Robert A Blake, Frederick Cohen, Terry D Crawford, Joy Drobnick, Jason Drummond, Lorna Kategaya, Tracy Kleinheinz, Till Maurer, Lionel Rougé, Xianrui Zhao, Ingrid Wertz, Chudi Ndubaku, Vickie Tsui
USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53, and for this reason it has gained increasing attention as a potential oncology target for small molecule inhibitors. Herein we describe the biophysical, biochemical, and computational approaches that led to the identification of 4-(2-aminopyridin-3-yl)phenol compounds described by Kategaya ( Nature 2017 , 550 , 534 - 538 ) as specific inhibitors of USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual screening and re-mining of biochemical high-throughput screening (HTS) hits led to the discovery of a series of ligands that bind in the "palm" region of the catalytic domain of USP7 and inhibit its catalytic activity...
December 28, 2017: Journal of Medicinal Chemistry
Xi Zhang, Terry Walsh, John J Atherton, Karam Kostner, Benjamin Schulz, Chamindie Punyadeera
BACKGROUND: Over 26 million people suffer from heart failure (HF) globally. Current diagnosis of HF relies on clinical evaluation, blood assays and imaging techniques. Our aim is to develop a diagnostic assay to detect HF in at risk individuals within the community using human saliva as a medium, potentially leading to a simple, safe early warning system. METHODS: Saliva samples were collected from healthy controls (n=36) and HF patients (n=75). Salivary proteome profiles were analysed by Sequential Window Acquisition of All Theoretical fragment ion spectra - Mass Spectrometry (SWATH-MS)...
2017: Theranostics
Magfur E Alam, Steven B Geng, Christian Bender, Seth D Ludwig, Lars Linden, Rene Hoet, Peter M Tessier
In vitro antibody discovery and/or affinity maturation are often performed using antibody fragments (Fabs), but most monovalent Fabs are reformatted as bivalent IgGs (monoclonal antibodies, mAbs) for therapeutic applications. One problem related to reformatting antibodies is that the bivalency of mAbs can lead to increased antibody self-association and poor biophysical properties (e.g., reduced antibody solubility and increased viscosity). Therefore, it is important to identify monovalent Fabs early in the discovery and/or optimization process that will display favorable biophysical properties when reformatted as bivalent mAbs...
January 2, 2018: Molecular Pharmaceutics
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