Abstract：
:Identifying local similarities in binding sites from distant proteins is a major hurdle to rational drug design. We herewith present a novel method, borrowed from computer vision, adapted to mine fragment subpockets and compare them to whole ligand-binding sites. Pockets are represented by pharmacophore-annotated point clouds mimicking ideal ligands or fragments. Point cloud registration is used to find the transformation enabling an optimal overlap of points sharing similar topological and pharmacophoric neighborhoods. The method (ProCare) was calibrated on a large set of druggable cavities and applied to the comparison of fragment subpockets to entire cavities. A collection of 33,953 subpockets annotated with their bound fragments was screened for local similarity to cavities from recently described protein X-ray structures. ProCare was able to detect local similarities between remote pockets and transfer the corresponding fragments to the query cavity space, thereby proposing a first step to fragment-based design approaches targeting orphan cavities.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Eguida M,Rognan Ddoi
10.1021/acs.jmedchem.0c00422subject
Has Abstractpub_date
2020-07-09 00:00:00pages
7127-7142issue
13eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章abstract：:Thirteen newly synthesized or resynthesized diamine-platinum(II) complexes were characterized, and their cytotoxic activities (IC50) were tested on parental and resistant ovarian cancer cell lines. They represent models of conjugates between biologically active vectors and cytotoxic Pt(II) moieties within the "drug ta...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049508t
更新日期：2005-02-10 00:00:00
abstract：:Using the crystal structure of an inhibitor complexed with the serine protease thrombin (PDB code ) and the functional group definitions contained within the Catalyst software, a representation of the enzyme's active site was produced (structure-based pharmacophore model). A training set of 16 homologous non-peptide i...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm021028j
更新日期：2003-04-10 00:00:00
abstract：:Synthetic routes were developed to access a variety of novel 1-aryl-2H,4H-tetrahydro-1,2,4-triazin-3-one analogs which were evaluated as 5-lipoxygenase (5-LO) inhibitors. The parent structure, 1-phenylperhydro-1,2,4-triazin-3-one (4), was found to be a selective inhibitor of 5-LO in broken cell, intact cell, and human...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960372b
更新日期：1996-09-27 00:00:00
abstract：:The protein kinase PfCLK3 plays a critical role in the regulation of malarial parasite RNA splicing and is essential for the survival of blood stage Plasmodium falciparum. We recently validated PfCLK3 as a drug target in malaria that offers prophylactic, transmission blocking, and curative potential. Herein, we descri...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00451
更新日期：2020-09-10 00:00:00
abstract：:A structure-activity study was performed to examine the role of position 14 of human alpha-calcitonin gene-related peptide (h-alpha-CGRP) in activating the CGRP receptor. Interestingly, position 14 of h-alpha-CGRP contains a glycyl residue and is part of an alpha-helix spanning residues 8-18. Analogues [Ala14]-h-alpha...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9608164
更新日期：1997-09-12 00:00:00
abstract：:The family of homodimeric nitric oxide synthases (NOS I-III) catalyzes the generation of the cellular messenger nitric oxide (NO) by oxidation of the substrate L-arginine. The rational design of specific NOS inhibitors is of therapeutic interest in regulating pathological NO levels associated with sepsis, inflammatory...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020074g
更新日期：2002-07-04 00:00:00
abstract：:Multidrug-resistant Staphylococcus aureus, including MRSA (methicillin-resistant) and VRSA (vancomycin-resistant), causes serious healthcare-associated infections, even sepsis and death. Here, we identified six novel cathelicidins (CATHPb1-6) from Python bivittatu, and CATHPb1 displayed the best in vitro pharmacologic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00036
更新日期：2018-03-08 00:00:00
abstract：:C-terminal fragment analogues of the leech anticoagulant peptide hirudin represent a unique class of thrombin inhibitors that blocks thrombin's cleavage of fibrinogen but does not block the catalytic site of thrombin. In this paper, a series of synthetic peptides were prepared by solid-phase methodology to determine t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00400a020
更新日期：1988-05-01 00:00:00
abstract：:A number of new 4(1H)-quinazolinones were synthesized and evaluated in the carrageenin-induced paw edema test. Most of the compounds were obtained by the cyclization of the appropriately substituted anthranilamides with acid chlorides, followed by further chemical transformation. Structure-activity data suggest that 2...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm50001a006
更新日期：1985-05-01 00:00:00
abstract：:We report twelve analogues of [Pmp1,D-Trp2,Arg8]oxytocin, ANTAG (Pmp = beta, beta-pentamethylene-beta-mercaptopropionic acid), which is a potent antagonist (pA2 = 7.77) of the uterotonic effect of oxytocin (OT) in rats, as measured in a uterotonic assay. Nine of the following analogues were designed by replacement of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00111a025
更新日期：1991-07-01 00:00:00
abstract：:The synthesis of two new nucleotide analogues is described. 5'-Sulfamino-5'-deoxyadenosine (1) was prepared by reaction of 5'-amino-5'-deoxyadenosine with (CH3)3N.203, and 5'-sulfamino-5'-deoxythymidine (2) was prepared from 5'-amino-5'-deoxythymidine by a similar reaction. The 5'-sulfamino nucleosides are shown to be...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00205a024
更新日期：1978-07-01 00:00:00
abstract：:2,6-Dipeptidyl-anthraquinones are a promising class of nucleic acid-binding compounds that act as NC inhibitors in vitro. We designed, synthesized, and tested new series of 2,6-disubstituted-anthraquinones, which are able to bind viral nucleic acid substrates of NC. We demonstrate here that these novel derivatives int...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01494
更新日期：2016-03-10 00:00:00
abstract：:The cytotoxicities and DNA cross-linking abilities of several alkyl-substituted diaziridinylquinones have been investigated. The cytotoxicities were determined in DT-diaphorase-rich (H460 and HT29) and -deficient (H596 and BE) cell lines. It was shown that the cytotoxicities in these cell lines correlated with the rel...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm991007y
更新日期：1999-06-17 00:00:00
abstract：:4-Amino-5-arylpyrimidines were synthesized by a variety of methods and have demonstrated antiinflammatory activity in the carrageenan-induced edema in the rat but displayed little activity against adjuvant-induced arthritis in rats or against uv-induced erythema in guinea pigs. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00240a021
更新日期：1975-06-01 00:00:00
abstract：:The N- and C-terminal domains of human somatic angiotensin I converting enzyme (sACE-1) demonstrate distinct physiological functions, with resulting interest in the development of domain-selective inhibitors for specific therapeutic applications. Herein, the activity of lisinopril-coupled transition metal chelates was...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4009345
更新日期：2013-12-27 00:00:00
abstract：:Recently described biphenyl analogues of the antituberculosis drug PA-824 displayed improved potencies against M. tuberculosis but were poorly soluble. Heterobiaryl analogues of these, in which the first phenyl ring was replaced with various 5-membered ring heterocycles, were prepared with the aim of identifying poten...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901378u
更新日期：2010-01-28 00:00:00
abstract：:The bioavailability of aromatic azaheterocyclic drugs can be affected by the activity of aldehyde oxidase (AO). Susceptibility to AO metabolism is difficult to predict computationally and can be complicated in vivo by differences between species. Here we report the use of bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4017976
更新日期：2014-02-27 00:00:00
abstract：:The synthesis of 5-(arylacetyl)-4-[(alkylamino)methyl]furo[3,2-c] pyridines (16-23, 26, 27) and their activities as kappa-opioid receptor agonists are described. kappa-Agonist potency was particularly sensitive to the nature of the basic moiety. In particular, in the rabbit vas deferens (kappa-specific tissue), the 3-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00040a004
更新日期：1994-07-08 00:00:00
abstract：:Macrophage migration inhibitory factor (MIF) is a cytokine with key roles in inflammation and cancer, which qualifies it as a potential drug target. Apart from its cytokine activity, MIF also harbors enzyme activity for keto-enol tautomerization. MIF enzymatic activity has been used for identification of MIF binding m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01160
更新日期：2020-10-22 00:00:00
abstract：:Molecular modeling methods have been used to design a novel series of conformationally constrained cyclic peptide inhibitors of human renin. Three goals were defined: enhanced inhibitory potency, high specificity for renin, and increased metabolic stability. Three cyclic compounds were synthesized with ring sizes 10, ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00397a003
更新日期：1988-02-01 00:00:00
abstract：:A novel series of 3,4-dihydroxychalcones was synthesized to evaluate their effects against 5-lipoxygenase and cyclooxygenase. Almost all compounds exhibited potent inhibitory effects on 5-lipoxygenase with antioxidative effects, and some also inhibited cyclooxygenase. The 2',5'-disubstituted 3,4-dihydroxychalcones wit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00076a019
更新日期：1993-11-26 00:00:00
abstract：:Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention toward that go...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00898
更新日期：2020-03-12 00:00:00
abstract：:A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]cloni...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00375a017
更新日期：1984-09-01 00:00:00
abstract：:Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells undergoing a stress response. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00098
更新日期：2015-03-26 00:00:00
abstract：:An essential step in the HIV life cycle is integration of the viral DNA into the host chromosome. This step is catalyzed by a 32-kDa viral enzyme HIV integrase (IN). HIV-1 IN is an important and validated target, and the drugs that selectively inhibit this enzyme, when used in combination with reverse transcriptase (R...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030378i
更新日期：2004-01-15 00:00:00
abstract：:Syntheses of several tripeptide analogues of leupeptin containing C-terminal argininal, lysinal, or ornithinal units are presented. The synthetic analogues were tested as inhibitors of trypsin, plasmin, and kallikrein. (Benzyloxycarbonyl)-L-leucyl-L-leucyl-L-argininal (2a) was significantly less effective as an inhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00163a014
更新日期：1990-01-01 00:00:00
abstract：:Activation of the IRE-1/XBP-1 pathway has been linked to many human diseases. We report a novel fluorescent tricyclic chromenone inhibitor, D-F07, in which we incorporated a 9-methoxy group onto the chromenone core to enhance its potency and masked the aldehyde to achieve long-term efficacy. Protection of the aldehyde...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00269
更新日期：2019-06-13 00:00:00
abstract：:Based on the known biological activity of a variety of guanidine-containing agents, several N-substituted 3,4-dihydroquinazolines were synthesized. These compounds can be considered to be rigid analogues of phenylguanidines. In anesthetized rats the compounds decreased blood pressure and were antagonists of the presso...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00185a026
更新日期：1980-11-01 00:00:00
abstract：:The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (alphaMSH) and its analogs, causes a decrease in food intake and elevates energy utilization upon binding to the melanocortin-4 receptor (MC4R). To utilize this sequence as an effective agent for treating obesity, we improved its me...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm701093y
更新日期：2008-02-28 00:00:00
abstract：:S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules wit...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00928
更新日期：2015-12-10 00:00:00
