Abstract:
:Recently, the binding kinetics of a ligand-target interaction, such as the residence time of a small molecule on its protein target, are seen as increasingly important for drug efficacy. Here, we investigate these concepts to explain binding and proton blockage of rimantadine variants bearing progressively larger alkyl groups to influenza A virus M2 wild type (WT) and M2 S31N protein proton channel. We showed that resistance of M2 S31N to rimantadine analogues compared to M2 WT resulted from their higher koff rates compared to the kon rates according to electrophysiology (EP) measurements. This is due to the fact that, in M2 S31N, the loss of the V27 pocket for the adamantyl cage resulted in low residence time inside the M2 pore. Both rimantadine enantiomers have similar channel blockage and binding kon and koff against M2 WT. To compare the potency between the rimantadine variants against M2, we applied approaches using different mimicry of M2, i.e., isothermal titration calorimetry and molecular dynamics simulation, EP, and antiviral assays. It was also shown that a small change in an amino acid at site 28 of M2 WT, which does not line the pore, seriously affects M2 WT blockage kinetics.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Drakopoulos A,Tzitzoglaki C,McGuire K,Hoffmann A,Konstantinidi A,Kolokouris D,Ma C,Freudenberger K,Hutterer J,Gauglitz G,Wang J,Schmidtke M,Busath DD,Kolocouris Adoi
10.1021/acsmedchemlett.7b00458subject
Has Abstractpub_date
2018-01-29 00:00:00pages
198-203issue
3issn
1948-5875journal_volume
9pub_type
杂志文章abstract::A new prosthetic group referred to as the triazole appending agent (TAAG) was developed as a means to prepare targeted radioiodine-based molecular imaging and therapy agents. Tributyltin-TAAG and the fluorous analogue were synthesized in high yield using simple click chemistry and the products labeled in greater than ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300003v
更新日期:2012-02-18 00:00:00
abstract::Here, we predicted the potential halogen bonding interaction between compound 2 and the 5-hydroxytryptamine 2B (5-HT2B) receptor and systematically assessed this interaction via structure-activity relationship analysis and molecular dynamics simulations. A physics-based computational protocol was then developed to fur...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00300
更新日期:2018-10-01 00:00:00
abstract::Substitution of rigidified A3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in p...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00150
更新日期:2015-05-20 00:00:00
abstract::The influence of ionization states of hydroxamates and retrohydroxamates and the presence of zinc ions in the active site were investigated using the wild-type and E402Q mutant of MMP-9. The deprotonated hydroxamates showed a significantly enhanced enrichment factor in the presence of zinc ions. A pharmacophore model ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200031m
更新日期:2011-03-29 00:00:00
abstract::S-Nitrosoglutathione reductase (GSNOR) regulates S-nitrosothiols (SNOs) and nitric oxide (NO) in vivo through catabolism of S-nitrosoglutathione (GSNO). GSNOR and the anti-inflammatory and smooth muscle relaxant activities of SNOs, GSNO, and NO play significant roles in pulmonary, cardiovascular, and gastrointestinal ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200045s
更新日期:2011-03-11 00:00:00
abstract::Reactive oxygen species, contributing to oxidant-antioxidant imbalance, initiate damage to the airways cells, inflammatory processes, and further pathophysiological effects. Enhancing antioxidant properties is the main prophylactic and therapeutic challenge. In this work, a newly synthesized and biocompatible structur...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00468
更新日期:2018-11-19 00:00:00
abstract::Protein thermal shift assays (TSAs) provide a means for characterizing target engagement through ligand-induced thermal stabilization. Although these assays are widely utilized for screening libraries and validating hits in drug discovery programs, they can impose encumbering operational requirements, such as the avai...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00081
更新日期:2018-04-16 00:00:00
abstract::Synthesis of a strict structural analogue of albaconazole in which the quinazolinone ring is fused by a thiazole moiety led to the discovery of a new triazole with broad-spectrum antifungal activity. Compound I exhibited high in vitro activity against pathogenic Candida species and filamentous fungi and showed prelimi...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300429p
更新日期:2013-01-17 00:00:00
abstract::A series of urea/thiourea substituted benzoxaboroles was investigated for the inhibition of the three carbonic anhydrases encoded by Vibrio cholerae (VchCAα, VchCAβ, and VchCAγ). In particular, benzoxaborole derivatives were here first assayed for the inhibition of a γ-class CA, extending the panel of CA classes that ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00403
更新日期:2020-09-09 00:00:00
abstract::Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor 11 resulted to be the most potent one with Ki values of 0.49 and 0.44 nM against rhodesain and cruzain, respectively. According to enzymatic dilution and dialysis experiments, as well as computational and NMR studies, dipeptidyl ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00276
更新日期:2016-09-21 00:00:00
abstract::A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a-m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racem...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00205
更新日期:2017-06-21 00:00:00
abstract::A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure-activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00247
更新日期:2015-07-20 00:00:00
abstract::A focused multiply N-methylated library of a cyclic hexapeptidic somatostatin analogue: MK678 cyclo(-MeAYwKVF-) was generated, which resulted in the unexpected observation of an efficacious tetra-N-methylated analogue, cyclo(-MeAYMewMeKVMeF-) with a potent inhibitory action on sensory neuropeptide release in vitro and...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200032v
更新日期:2011-04-04 00:00:00
abstract::Collaborations between the pharmaceutical industry and contract research organizations continue to represent an attractive alternative to internal drug discovery within a single organization. This Viewpoint covers many of the business models and strategies that are employed in industry-contract research organization c...
journal_title:ACS medicinal chemistry letters
pub_type: 社论
doi:10.1021/acsmedchemlett.8b00236
更新日期:2018-06-04 00:00:00
abstract::A series of novel aminopyridyl/pyrazinyl-substituted spiro[indoline-3,4'-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1'-methylspiro[indoline-3,4'-piperidine]-2-one (compo...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400203d
更新日期:2013-07-12 00:00:00
abstract::A novel series of quinazolinone T-type calcium channel antagonists have been prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 by modifications of the 3- and 4-positions of the quinazolinone ring afforded potent and selective antagonists that displayed in vivo central nervou...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100004r
更新日期:2010-02-01 00:00:00
abstract::A series of novel selenides bearing benzenesulfonamide moieties was synthesized and investigated for their inhibition on six human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms such as the physiologically relevant hCA I, II, VA, VB, VII, and IX and the X-ray complex in adduct with hCA II for some of them investigat...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00076
更新日期:2018-04-09 00:00:00
abstract::In this study the μ opioid receptor (MOR) ligands DALDA (Tyr-d-Arg-Phe-Lys-NH2) and Dmt1-DALDA (Dmt-d-Arg-Phe-Lys-NH2, Dmt = 2',6'-dimethyltyrosine) were glycosylated at the N- or C-terminus. Subsequently, the modified peptides were subjected to in vitro and in vivo evaluation. In contrast to the N-terminally modified...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml4004765
更新日期:2014-04-10 00:00:00
abstract::Replication protein A (RPA) is the major human single stranded DNA (ssDNA)-binding protein, playing essential roles in DNA replication, repair, recombination, and DNA-damage response (DDR). Inhibition of RPA-DNA interactions represents a therapeutic strategy for cancer drug discovery and has great potential to provide...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00440
更新日期:2020-01-02 00:00:00
abstract::Tak-242 (resatorvid), a Toll-like Receptor 4 (TLR4) inhibitor, has been identified as a potent suppressor of innate inflammation. As a strategy to target Tak-242 to select tissue, four TLR4-inactive prodrugs were synthesized for activation via two different release mechanisms. Two nitrobenzyl Tak-242 prodrugs released...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00518
更新日期:2020-01-03 00:00:00
abstract::APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/P...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500389m
更新日期:2014-11-04 00:00:00
abstract::Abdominal pain and abnormal bowel habits represent major symptoms for irritable bowel syndrome (IBS) patients that are not adequately managed. Although the etiology of IBS is not completely understood, many of the functions of the gastrointestinal (GI) tract are regulated by the enteric nervous system (ENS). Inflammat...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00035
更新日期:2018-05-24 00:00:00
abstract::EPAC proteins are therapeutic targets for the potential treatment of cardiac hypertrophy and cancer metastasis. Several laboratories use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1 in various disease states. Here, we report SAR studies with tetrahydroquinoline analogs that explore various functio...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00358
更新日期:2017-10-02 00:00:00
abstract::Structure-based design methods commonly used in medicinal chemistry rely on a three-dimensional representation of the receptor. However, few crystal structures are solved in comparison with the huge number of pharmaceutical targets. This often renders homology models the only information available. It is particularly ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100288q
更新日期:2011-02-11 00:00:00
abstract::A series of oxyguanidine analogues of the cysteine protease inhibitor WRR-483 were synthesized and evaluated against cruzain, the major cysteine protease of the protozoan parasite Trypanosoma cruzi. Kinetic analyses of these analogues indicated that they have comparable potency to previously prepared vinyl sulfone cru...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00336
更新日期:2015-12-15 00:00:00
abstract::GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclizati...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml1000855
更新日期:2010-06-18 00:00:00
abstract::The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cel...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00002
更新日期:2018-02-27 00:00:00
abstract::We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.1 nM). We also present a model...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500008w
更新日期:2014-03-11 00:00:00
abstract::Human mitogen-activated protein kinases (MAPK)-interacting kinases 1 and 2 (Mnk1/2) are promising anticancer targets. Mnks possess special insertions and a DFD-motif that are distinct from other kinases. Crystallographic studies of Mnk1/2 have revealed that the DFD-motif adopts the DFG/D-out conformation in which resi...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400145x
更新日期:2013-06-24 00:00:00
abstract::Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionali...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500030p
更新日期:2014-03-21 00:00:00