Abstract:
:Understanding subtle aspects of hydrogen bonding is a challenging but crucial task to improve our ability to design ligands with high affinity for protein hosts. To gain a deeper understanding of these aspects, we investigated a series of thrombin inhibitors in which the basicity of the ligand's group that accepts an H-bond from Gly216 was modulated via bioisosterism; e.g., a C=O acceptor was made electron deficient or rich via bioisosteric replacements of the adjacent moiety. Although the ligand's binding affinity was anticipated to improve when the H-bond basicity is increased (due to stronger H-bonding with the protein), we herein present data that unexpectedly revealed an opposite trend. This trend was attributed to a dominating role played by desolvation in determining the relative binding affinity. For example, a decrease in the H-bond basicity reduces the desolvation penalty and, as experimentally observed, improves the binding affinity, given that the reduction in the desolvation penalty dominates the change in the net contribution of the ligand's interactions with the protein. The current study, therefore, reveals that desolvation can be a major underlying cause for the apparently counterintuitive structure-activity relationship (SAR) outcomes, and indicates that understanding this factor can improve our ability to predict binding affinity and to design more potent ligands.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Nasief NN,Said AM,Hangauer Ddoi
10.1016/j.ejmech.2016.09.038subject
Has Abstractpub_date
2017-01-05 00:00:00pages
975-991eissn
0223-5234issn
1768-3254pii
S0223-5234(16)30768-1journal_volume
125pub_type
杂志文章abstract::Epidermal growth factor receptor (EGFR), a member of the HER family, is closely related to the development of multiple cancers. Herein, we report the discovery of small molecule EGFR degraders based on the proteolysis targeting chimera (PROTAC) strategy. In the present study, 13 EGFR degraders containing pyrido[3,4-d]...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112061
更新日期:2020-03-01 00:00:00
abstract::Human carboxylesterase 2 (hCE2), one of the major carboxylesterases in the human intestine and various tumour tissues, plays important roles in the oral bioavailability and treatment outcomes of ester- or amide-containing drugs or prodrugs, such as anticancer agents CPT-11 (irinotecan) and LY2334737 (gemcitabine). In ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2016.02.020
更新日期:2016-04-13 00:00:00
abstract::4'-((2-Propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid derived from telmisartan was identified as lead for the design of cell death modulators. In this study, we evaluated the efficacy of telmisartan itself and other sartans in combination with imatinib against K562-resistant cells. The findi...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2020.112258
更新日期:2020-06-01 00:00:00
abstract::Several novel semicarbazone derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde and semicarbazides bearing a spermidine-mimetic moiety. All derivatives presented the E-configuration, as determined by NMR-NOE experiments. These compounds were tested in vitro as potential antitrypan...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)00131-8
更新日期:2000-03-01 00:00:00
abstract::Semisynthetic 18β-glycyrrhetinic acid (GA) analogues bearing 1-en-2-cyano-3-oxo substitution on ring A have enhanced antitumor effects with reduced levels of HDAC3 and HDAC6 proteins. Aiming to inhibit both HDAC protein and activity, we developed a hybrid molecule by tethering active GA analogue methyl 2-cyano-3,11-di...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.111991
更新日期:2020-02-15 00:00:00
abstract::Carotenoids are natural pigments attracting attention of physicists, chemists and biologists due to their multiple functions in the nature. While carotenoids have unusually high extinction coefficients, they do not exhibit adequate emission. This fact has resulted in detailed studies of photophysical and photochemical...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2013.09.054
更新日期:2013-01-01 00:00:00
abstract::Vesicular Glutamate Transporters (VGLUTs) allow the loading of presynapic glutamate vesicles and thus play a critical role in glutamatergic synaptic transmission. VGLUTs have proved to be involved in several major neuropathologies and directly correlated to clinical dementia in Alzheimer and Parkinson's disease. Accor...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2014.03.056
更新日期:2014-05-06 00:00:00
abstract::The synthesis and pharmacological profiles of some new steroidal mono- and bisquaternary ammonium derivatives have been described. The compounds featured have been conceptually derived structurally from two lead structures: pancuronium bromide 1 and chandonium iodide 2. In vitro and in vivo neuromuscular blocking stud...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(00)01205-8
更新日期:2001-02-01 00:00:00
abstract::Metal complexes of 2-methyl-1H-benzimidazole-5-carboxylic acid hydrazide (4a; L(1)) and its Schiff base 2-methyl-N-(propan-2-ylidene)-1H-benzimidazole-5-carbohydrazide (5a; L(2)) with transition metal ions e.g., copper, silver, nickel, iron and manganese were prepared. The complexes formed were 1:1 or 1:2 M:L complexe...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2008.07.013
更新日期:2009-04-01 00:00:00
abstract::Leukotrienes (LTs) and prostaglandin (PG)E2, produced by 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), respectively, are key players in inflammation, and pharmacological suppression of these lipid mediators (LM) represents a strategy to intervene with inflammatory disorders. Previous stud...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.07.031
更新日期:2018-08-05 00:00:00
abstract::Bromodomain and plant homeodomain (PHD) finger containing protein 1 (BRPF1) is a member of subfamily IV of the human bromodomains. Experimental evidence suggests that BRPF1 is involved in leukemia. In a previous high-throughput docking campaign we identified several chemotypes targeting the BRPF1 bromodomain. Here, ph...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2018.05.037
更新日期:2018-07-15 00:00:00
abstract::Synthesis of a series of urea/thiourea/acetamide/sulphonamide derivatives of quinazolinones conjugated lysine has been reported. Structures of the products have been determined by standard spectroscopical studies. All the compounds have been screened for their antibacterial studies and structure-activity relationship ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.03.041
更新日期:2011-06-01 00:00:00
abstract::Several 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles were prepared by condensation of 4-amino-5-substituted-3-mercapto-(4H)-1,2,4-triazoles (3a,b) with various substituted aromatic acids and aryl/alkyl isothiocyanates through a one-pot reaction. These compounds were investigated for their anti-inflammat...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2007.09.025
更新日期:2008-10-01 00:00:00
abstract::This work deals with the synthesis and evaluation of new compounds designed by combination of 1,4-naphthoquinone and ferrocene fragments in a 3-ferrocenylmethyl-2-hydroxy-1,4-naphthoquinone arrangement. A practical coupling reaction between 2-hydroxy-1,4-naphthoquinone and ferrocenemethanol derivatives has been develo...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2013.10.011
更新日期:2013-01-01 00:00:00
abstract::Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.12.024
更新日期:2016-01-27 00:00:00
abstract::The work describes a discovery of new chemical family of potent ligands for the 5-HT6 serotonin receptors. During the search for new histamine H4 receptor antagonists among 1,3,5-triazine derivatives, compound 2 (4-benzyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) was found. Compound 2, weakly active for the H4...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2017.04.033
更新日期:2017-07-28 00:00:00
abstract::The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (Mpro) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2017.05.045
更新日期:2017-09-08 00:00:00
abstract::Effective photosensitizers are particularly important factor in clinical photodynamic therapy (PDT). However, there is a scarcity of photosensitizers for simultaneous cancer photo-diagnosis and targeted PDT. Herein, two novel dimethyl 2-(guanidinyl)ethylamino chlorin e6 photosensitizers were synthesized and their effi...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.05.050
更新日期:2019-09-01 00:00:00
abstract::To define the SAR, a series of novel N-arylsulfonylimidazolidinone derivatives were evaluated for their in vitro anticancer activity against five human tumor cell lines, including A549, COLO205, KATO III, K562, SK-OV-3 and murine leukemia (P288D1) cell line. Among them, N-(2-chloroacetyl)-6-(2-oxo-4-phenylimidazolidin...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.04.042
更新日期:2011-08-01 00:00:00
abstract::Levamisole, the imidazo[2,1-b]thiazole derivative has been reported as a potential antitumor agent. In the present study, we synthesized, characterized and evaluated biological activity of its novel analogues with substitution in the aralkyl group and on imidazothiadiazole molecules with same chemical backbone but dif...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.02.064
更新日期:2011-06-01 00:00:00
abstract::Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2019.111652
更新日期:2019-11-15 00:00:00
abstract::Oral absorption of compounds depends on many physiological, physiochemical and formulation factors. Two important properties that govern oral absorption are in vitro permeability and solubility, which are commonly used as indicators of human intestinal absorption. Despite this, the nature and exact characteristics of ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2014.12.006
更新日期:2015-01-27 00:00:00
abstract::A series of novel 1,4-pentadien-3-one derivatives containing 4-thioquinazoline moiety were designed and synthesized. Antiviral bioassay results indicated that most of the title compounds exhibited excellent antiviral activities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) in vivo. Among the title...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.08.029
更新日期:2015-09-18 00:00:00
abstract::Oxyprenylated secondary metabolites from plants, fungi, and bacteria, and their semisynthetic derivatives have been subject of growing interest during the last decade. Such natural products in fact have been discovered as potentially novel lead compounds for a series of pharmacological activities, mainly in terms of a...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2017.08.038
更新日期:2018-06-10 00:00:00
abstract::Boron neutron capture therapy (BNCT) is an experimental treatment modality which depends on a sufficient cellular uptake of Boron ((10)B) followed by an exposure to a thermal neutron beam from a nuclear reactor. High energetic particles (4He and 7Li) are created during the neutron capture reaction and produce DNA dama...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/s0223-5234(03)00088-6
更新日期:2003-06-01 00:00:00
abstract::Three new series of quinoline-4-yl-1,2,3-triazoles carrying amides, sulphonamides and amidopiperazines were synthesized through multi-step reactions. The required intermediate, [1-(6-methoxy-2-methylquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methanol (2) was prepared by treating 4-azido-6-methoxy-2-methylquinoline (1) with ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2011.03.039
更新日期:2011-06-01 00:00:00
abstract::Oxindole has emerged as a valuable scaffold in medicinal chemistry possessing diverse range of pharmacological activities. Its value has further been increased by its natural occurrence as alkaloids in variety of plants. It was first extracted from the cat claw's plant Uncaria tomentosa found in the Amazon rainforest ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1016/j.ejmech.2016.08.011
更新日期:2016-11-10 00:00:00
abstract::A series of novel di- or trisubstituted isatin derivatives were designed and synthesized in 5-6 steps in 25-45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC-MS. The anticancer activity of the fourty-three new isatin derivatives against human T lymphocyte cells Jurkat was evaluate...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2015.12.050
更新日期:2016-04-13 00:00:00
abstract::NEDD8 activating enzyme (NAE) plays a critical role in various cellular functions in cancers. In this study, a target-based virtual screening was applied to discover benzothiazoles to be potent non-covalent NAE inhibitors. Further two round optimizations concluded a preliminary structure-activity relationship (SAR) of...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2017.03.076
更新日期:2017-06-16 00:00:00
abstract::Novel ester prodrugs (II, III and IV) of ibuprofen (I) were synthesized using alpha-methyl, ethyl and propyl glucopyranoside as promoieties and tested for their anti-inflammatory, analgesic and ulcerogenic activities. Study of their chemical hydrolysis in aqueous buffer (pH 3.0-10.0) showed that these compounds acted ...
journal_title:European journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1016/j.ejmech.2006.05.014
更新日期:2006-11-01 00:00:00