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Fragment Based Lead Discovery

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https://www.readbyqxmd.com/read/29448139/discovery-and-optimization-of-1-1h-indol-1-yl-ethanone-derivatives-as-cbp-ep300-bromodomain-inhibitors-for-the-treatment-of-castration-resistant-prostate-cancer
#1
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
https://www.readbyqxmd.com/read/29388326/discovery-of-novel-5-methyl-1h-pyrazole-derivatives-as-potential-anti-prostate-cancer-agents-design-synthesis-molecular-modeling-and-biological-evaluation
#2
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
https://www.readbyqxmd.com/read/29378408/small-molecule-inhibitors-of-the-pcsk9%C3%A2-ldlr-interaction
#3
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 no 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...
January 29, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29378316/fragment-screening-for-drug-leads-by-weak-affinity-chromatography-wac-ms
#4
REVIEW
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
https://www.readbyqxmd.com/read/29328649/phenylthiomethyl-ketone-based-fragments-show-selective-and-irreversible-inhibition-of-enteroviral-3c-proteases
#5
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...
January 12, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29306387/attitudes-and-perceptions-of-radiographers-applying-lead-pb-protection-in-general-radiography-an-ethnographic-study
#6
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
https://www.readbyqxmd.com/read/29281288/reverse-and-random-decoy-methods-for-false-discovery-rate-estimation-in-high-mass-accuracy-peptide-spectral-library-searches
#7
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, in this paper we report the development and validation of methods for high mass accuracy decoy libraries...
December 27, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/29259745/identification-of-an-indazole-based-pharmacophore-for-the-inhibition-of-fgfr-kinases-using-fragment-led-de-novo-design
#8
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
https://www.readbyqxmd.com/read/29193967/structure-guided-discovery-of-novel-potent-and-orally-bioavailable-inhibitors-of-lipoprotein-associated-phospholipase-a2
#9
Qiufeng Liu, Fubao Huang, Xiao-Jing 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 300-fold potency improvement. 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 activity were obtained...
December 1, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29166018/discovery-of-small-molecule-inhibitors-of-ubiquitin-specific-protease-7-usp7-using-integrated-nmr-and-in-silico-techniques
#10
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 Rouge, 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 et al.1 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...
November 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29158831/identification-and-validation-of-a-salivary-protein-panel-to-detect-heart-failure-early
#11
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
https://www.readbyqxmd.com/read/29154550/biophysical-and-sequence-based-methods-for-identifying-monovalent-and-bivalent-antibodies-with-high-colloidal-stability
#12
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...
November 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29150397/fragment-based-design-synthesis-biological-evaluation-and-sar-of-1h-benzo-d-imidazol-2-yl-1h-indazol-derivatives-as-potent-pdk1-inhibitors
#13
Ting Chen, Venkataswamy Sorna, Susie Choi, Lee Call, Jared Bearss, Kent Carpenter, Steven L Warner, Sunil Sharma, David J Bearss, Hariprasad Vankayalapati
In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC50 of 80 nM and 94 nM, respectively...
October 28, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29143719/microbial-protein-targets-towards-understanding-and-intervention
#14
Paul W Denny
The rise of antimicrobial resistance, coupled with a lack of industrial focus on antimicrobial discovery over preceding decades, has brought the world to a crisis point. With both human and animal health set to decline due to increased disease burdens caused by near untreatable microbial pathogens, there is an urgent need to identify new antimicrobials. Central to this is the elucidation of new, robustly validated, drug targets. Informed by industrial practice and concerns, the use of both biological and chemical tools in validation is key...
November 16, 2017: Parasitology
https://www.readbyqxmd.com/read/29118093/current-perspectives-in-fragment-based-lead-discovery-fbld
#15
REVIEW
Bas Lamoree, Roderick E Hubbard
It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most 'conventional' targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein-protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery - generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29111727/bioisostere-identification-by-determining-the-amino-acid-binding-preferences-of-common-chemical-fragments
#16
Tomohiro Sato, Noriaki Hashimoto, Teruki Honma
To assist the structural optimization of hit/lead compound during drug discovery, various computational approaches to identify potentially useful bioisosteric conversions have been reported. Here, the preference of chemical fragments to hydrogen bond with specific amino acid residues was used to identify potential bioisosteric conversions. We first compiled a data set of chemical fragments frequently occurring in complex structures contained in Protein Data Bank. We then used a computational approach to determine the amino acids to which these chemical fragments most frequently hydrogen bonded...
November 7, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29111368/discovery-of-new-antimalarial-agents-second-generation-dual-inhibitors-against-fp-2-and-pfdhfr-via-fragments-assembely
#17
Wenhua Chen, Zhenghui Huang, Wanyan Wang, Fei Mao, Longfei Guan, Yun Tang, Hualiang Jiang, Jian Li, Jin Huang, Lubin Jiang, Jin Zhu
Malaria parasites are a leading cause of worldwide mortality from infectious disease. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) play vital roles, which are absolutely essential, in the parasite life cycle. In this study, based on the structures of uniform fragments of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the discovery of 24, which showed high potency against FP-2 (IC50 = 10...
October 16, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29095571/generative-recurrent-networks-for-de-novo-drug-design
#18
Anvita Gupta, Alex T Müller, Berend J H Huisman, Jens A Fuchs, Petra Schneider, Gisbert Schneider
Generative artificial intelligence models present a fresh approach to chemogenomics and de novo drug design, as they provide researchers with the ability to narrow down their search of the chemical space and focus on regions of interest. We present a method for molecular de novo design that utilizes generative recurrent neural networks (RNN) containing long short-term memory (LSTM) cells. This computational model captured the syntax of molecular representation in terms of SMILES strings with close to perfect accuracy...
November 2, 2017: Molecular Informatics
https://www.readbyqxmd.com/read/29070410/exploring-natural-product-fragments-for-drug-and-probe-discovery
#19
Axel Pahl, Herbert Waldmann, Kamal Kumar
Fragment-based ligand discovery is a key technology to develop lead structures for drug discovery. The majority of the fragments employed so far is aromatic and sp2-configured, and there is a high demand of fragments with stereogenic centers. Natural products (NPs) are evolutionary selected ligands for a range of diverse macromolecular targets. Small-sized molecules - fragments - based on NPs may inherit the biological relevance of nature's treasure and could offer novel opportunities to engage challenging protein targets...
October 25, 2017: Chimia
https://www.readbyqxmd.com/read/28940929/allosteric-tuning-of-caspase-7-a-fragment-based-drug-discovery-approach
#20
Nicholas R Vance, Lokesh Gakhar, M Ashley Spies
The caspase family of cysteine proteases are highly sought-after drug targets owing to their essential roles in apoptosis, proliferation, and inflammation pathways. High-throughput screening efforts to discover inhibitors have gained little traction. Fragment-based screening has emerged as a powerful approach for the discovery of innovative drug leads. This method has become a central facet of drug discovery campaigns in the pharmaceutical industry and academia. A fragment-based drug discovery campaign against human caspase-7 resulted in the discovery of a novel series of allosteric inhibitors...
November 13, 2017: Angewandte Chemie
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