Abstract:
:A DNA-encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity. Molecules based on a 3,5-bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a Kd value of 6 nm, while compounds with the same substituents on an equidistant but flexible l-lysine scaffold showed 140-fold lower affinity. A 18 nm tankyrase-1 binder featured l-lysine as linking moiety, while molecules based on d-Lysine or (2S,4S)-amino-l-proline showed no detectable binding to the target. This work suggests that central scaffolds which predispose the orientation of chemical building blocks toward the protein target may enhance the screening productivity of encoded libraries.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Favalli N,Biendl S,Hartmann M,Piazzi J,Sladojevich F,Gräslund S,Brown PJ,Näreoja K,Schüler H,Scheuermann J,Franzini R,Neri Ddoi
10.1002/cmdc.201800193subject
Has Abstractpub_date
2018-07-06 00:00:00pages
1303-1307issue
13eissn
1860-7179issn
1860-7187journal_volume
13pub_type
杂志文章相关文献
ChemMedChem文献大全abstract::Metalloproteinases of the astacin family are drawing ever increasing attention as potential drug targets. However, knowledge regarding inhibitors thereof is limited in most cases. Crucial for the development of metalloprotease inhibitors is high selectivity, to avoid side effects brought about by inhibition of off-tar...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800300
更新日期:2018-08-20 00:00:00
abstract::We report the synthesis of trifluoromethylated metallocenes (M=Fe, Ru) and related metal-free compounds for comparison of their biological properties with the aim to establish structure-activity relationships toward the anti-proliferative activity of this compound class. All new compounds were comprehensively characte...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201402001
更新日期:2014-06-01 00:00:00
abstract::Intraoperative imaging technologies recently entered the operating room, and their implementation is revolutionizing how physicians plan, monitor, and perform surgical interventions. In this work, we present a novel surgical imaging reporter system: intraoperative chemiluminescence imaging (ICI). To this end, we have ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600301
更新日期:2016-09-20 00:00:00
abstract::Because only a few studies have investigated the affinity and functional activity of NMDA receptor open channel blockers under the same assay conditions, a comparative study of common open channel blockers is of major interest. The pharmacological activities of MK-801, phencyclidine (PCP), dexoxadrol, etoxadrol, (S)- ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700810
更新日期:2018-03-06 00:00:00
abstract::The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electro...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900112
更新日期:2019-05-06 00:00:00
abstract::Pharmaceutical companies are facing an increasing interest in new target identification and validation. In particular, extensive efforts are being made in the field of protein kinase inhibitors research and development, and the past ten years of effort in this field have altered our perception of the potential of kina...
journal_title:ChemMedChem
pub_type: 杂志文章,评审
doi:10.1002/cmdc.200600271
更新日期:2007-08-01 00:00:00
abstract::Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis of cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treat...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900014
更新日期:2009-05-01 00:00:00
abstract::We recently reported the synthesis and biological evaluation of a novel series of 5-alkyl-2-(N,N-disubstituted)amino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones (F(2)-N,N-DABOs). These compounds are highly active against both wild-type HIV-1 and the K103N, Y181C, and Y188L mutant strains. Herein we pre...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200800051
更新日期:2008-09-01 00:00:00
abstract::Targeting LRH-1: Virtual screening and molecular modeling were used to identify novel antagonists of liver receptor homolog-1 (LRH-1), an emerging therapeutic target for breast cancer. Hit compounds were synthesized and biologically assayed, and the preliminary results suggest that raloxifene-based analogues, substitu...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200307
更新日期:2012-11-01 00:00:00
abstract::Unraveling the mechanisms involved in castration- and therapy-resistant prostate cancer has led to a renewed interest in androgen receptor (AR)-targeted therapeutics. Anti-androgens that block the activity of the AR therefore remain a valid therapeutic option. However, they must be more effective than, or display a di...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200549
更新日期:2013-04-01 00:00:00
abstract::The less polar π-surface of protein amide groups is exposed in many receptor binding sites, either as part of the backbone or in Gln/Asn side chains. Using quantum chemical calculations and Protein Data Bank (PDB) searches on model systems, we investigate the energetics and geometric preferences for the stacking on am...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200512
更新日期:2013-03-01 00:00:00
abstract::Nuclear magnetic resonance (NMR) spectroscopy is a valuable technique for ligand screening, because it exhibits high specificity toward chemical structure and interactions. Dissolution dynamic nuclear polarization (DNP) is a recent advance in NMR methodology that enables the creation of non-equilibrium spin states, wh...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500241
更新日期:2015-09-01 00:00:00
abstract::Apelin is the endogenous ligand of the APJ receptor, a member of the G-protein-coupled receptor family. The apelin-APJ complex has been detected in many tissues and is emerging as a promising target for several pathophysiological conditions. There is currently little information on the structure-activity relationship ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100492
更新日期:2012-02-06 00:00:00
abstract::New geiparvarin derivatives modified at the unsaturated alkenyloxy bridge, where a hydrogen atom replaces the 3'-methyl group, were synthesized and evaluated against a panel of human tumor cell lines in vitro. These compounds demonstrated an increase in growth inhibitory activity relative to the parent compound, geipa...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200900009
更新日期:2009-05-01 00:00:00
abstract::β-Alanyl-D-histidine (D-CAR, the enantiomer of the natural dipeptide carnosine) is a selective and potent sequestering agent of reactive carbonyl species (RCS) that is stable against carnosinase, but is poorly absorbed in the gastrointestinal tract. Herein we report a drug discovery approach aimed at increasing the or...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201100042
更新日期:2011-07-04 00:00:00
abstract::The serotonin transporter (SERT) is one of the neurotransmitter transporters that plays a critical role in the regulation of endogenous amine concentrations and therefore is an important target for therapeutic agents affecting the central nervous system. The recently published, high resolution X-ray structure of the c...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600242
更新日期:2007-06-01 00:00:00
abstract::The renin angiotensin aldosterone system (RAAS) is a hormonal cascade involved in the regulation of blood pressure and electrolyte balance, and represents a common target for the treatment of various diseases including hypertension, heart failure, and diabetes. Herein we present a novel 18 F-labeled derivative of the ...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201800638
更新日期:2018-12-06 00:00:00
abstract::Having oxaliplatin as archetype, several platinum complexes with a carbohydrate moiety resembling the cyclohexane-1,2-diamine ligand of oxaliplatin have been prepared. As leaving groups, the anionic ligands iodide, oxalate, and malonate were utilized, and for comparison purposes the chloro complex was employed. All co...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.200600279
更新日期:2007-04-01 00:00:00
abstract::HIV protease is a promising drug target for AIDS therapy, and several potent HIV-1 protease inhibitors have been reported to date. Although existing inhibitors exhibit high selectivity, they have also been associated with severe side effects and the possible emergence of therapeutic resistance. As HIV protease cleaves...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201200271
更新日期:2012-09-01 00:00:00
abstract::Computer-guided drug design is a powerful tool for drug discovery. Herein we disclose the use of this approach for the discovery of dual FMS-like receptor tyrosine kinase-3 (FLT3)-Aurora A inhibitors against cancer. An Aurora hit compound was selected as a starting point, from which 288 virtual molecules were screened...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201300571
更新日期:2014-05-01 00:00:00
abstract::Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvβ1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identificati...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900359
更新日期:2019-07-17 00:00:00
abstract::Compound 11 (3-(benzyloxy)-1'-methyl-1'-azonia-4H-1'-azaspiro[isoxazole-5,3'-bicyclo[2.2.2]octane] iodide) was selected from a previous set of nicotinic ligands as a suitable model compound for the design of new silent agonists of α7 nicotinic acetylcholine receptors (nAChRs). Silent agonists evoke little or no channe...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700162
更新日期:2017-08-22 00:00:00
abstract::Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblast...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201700629
更新日期:2018-01-22 00:00:00
abstract::A screen of a focused kinase inhibitor library against Trypanosoma brucei rhodesiense led to the identification of seven series, totaling 121 compounds, which showed >50 % inhibition at 5 μm. Screening of these hits in a T. b. brucei proliferation assay highlighted three compounds with a 1H-imidazo[4,5-b]pyrazin-2(3H)...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500300
更新日期:2015-11-01 00:00:00
abstract::Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a small molecule with potent anticancer activity. Like other 1,4-naphthoquinones, it exhibits electrophilic reactivity towards biological nucleophiles. We demonstrate that plumbagin and structurally related 1,4-naphthoquinones with at least one unsubstituted quinoid...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000157
更新日期:2020-07-20 00:00:00
abstract::The clinical use of N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) has been hindered by its lack of bioavailability. N,N'-bis(2-boronic pinacol ester benzyl)ethylenediamine-N,N'-diacetic acid methyl, ethyl, and isopropyl esters 7 a-c, respectively, and their dimesylate salts 8 a-c, are double prodr...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600197
更新日期:2016-08-05 00:00:00
abstract::Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considere...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.202000564
更新日期:2020-10-08 00:00:00
abstract::The integrated stress response comprises multiple signaling pathways for detecting and responding to cellular stress that converge at a single event-the phosphorylation of Ser51 on the α-subunit of eukaryotic translation initiation factor 2 (eIF2α). Phosphorylation of eIF2α (eIF2α-P) results in attenuation of global p...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201500483
更新日期:2016-04-19 00:00:00
abstract::Two series of racemic goniothalamin analogues displaying nitrogen-containing groups were designed and synthesized. A total of 19 novel analogues were evaluated against a panel of four different cancer cell lines, along with the normal prostate cell line PNT2 to determine their selectivity. Among them, goniothalamin ch...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201900281
更新日期:2019-08-06 00:00:00
abstract::Numerous studies have shown that chalcones are promising scaffolds for the development of new monoamine oxidase-B (MAO-B) inhibitors. As a continuation of our ongoing research into the development of reversible human MAO-B (hMAO-B) inhibitors, two series of twenty chalcones containing electron-donating and electron-wi...
journal_title:ChemMedChem
pub_type: 杂志文章
doi:10.1002/cmdc.201600497
更新日期:2016-12-16 00:00:00