Abstract:
:A promising strategy for selecting synthetic targets is similarity-based searching of very large "virtual libraries", which comprise all structures accessible by linking two or three commercially available building blocks with combinatorial syntheses. To assess the general applicability of this strategy, leading structures taken from each of 34 recent medicinal chemistry publications were used as queries to search a virtual library containing 2.6 x 10(13) products from seven reactions, using a topomer shape similarity metric. Eighty-five percent of these searches succeeded, by yielding, with a search radius no greater than 120 topomer shape units, either at least 400 hits or hits from at least six sublibraries. From these 34 sets of search results, 122 representative structures were selected, illustrating potential "lead hops", or otherwise novel structures. Overall shape similarity to the query structure was confirmed for up to 95% of these representative structures, according to FLEXS, an algorithmically distinct program. Experimentally, there were 28 structures among those reported in the 34 query publications that were identified within the virtual library. Among these, the frequency of high activity was 87% for the 16 structures whose similarity to their query was 90 topomer units or less, compared to a frequency of 50% for the other 12 structures.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Andrews KM,Cramer RDdoi
10.1021/jm000003mkeywords:
subject
Has Abstractpub_date
2000-05-04 00:00:00pages
1723-40issue
9eissn
0022-2623issn
1520-4804pii
jm000003mjournal_volume
43pub_type
杂志文章abstract::The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallo...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm300334d
更新日期:2012-09-13 00:00:00
abstract::A group of oligopeptides has been synthesized that are structurally related to the natural antiviral antitumor agents netropsin and distamycin but which bear alkylating functions. Cytostatic activity against both human and murine tumor cell lines as well as their in vitro activity against a range of viruses is reporte...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00397a012
更新日期:1988-02-01 00:00:00
abstract::Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibito...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01869
更新日期:2018-04-26 00:00:00
abstract::We report the activities of 62 bisphosphonates as inhibitors of the Leishmania major mevalonate/isoprene biosynthesis pathway enzyme, farnesyl pyrophosphate synthase. The compounds investigated exhibit activities (IC(50) values) ranging from approximately 100 nM to approximately 80 microM (corresponding to K(i) values...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0302344
更新日期:2003-11-20 00:00:00
abstract::The synthesis and structure-activity relationships of a new class of vinylcephalosporins substituted with a lactamyl residue are described. These compounds show excellent activity against enterococci and retain the broad spectrum activity of third-generation cephalosporins such as ceftriaxone. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950886v
更新日期:1996-04-26 00:00:00
abstract::A series of 2- and 3-aminobenzanilides derived from ring-alkylated anilines were prepared and evaluated for anticonvulsant activity. These benzanilides were prepared in the course of studies designed to determine the relationship between the benzamide structure and anticonvulsant effects. The compounds were tested in ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00158a038
更新日期:1986-08-01 00:00:00
abstract::We present Fleksy, a new approach to consider both ligand and receptor flexibility in small molecule docking. Pivotal to our method is the use of a receptor ensemble to describe protein flexibility. To construct these ensembles, we use a backbone-dependent rotamer library and implement the concept of interaction sampl...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm070593p
更新日期:2007-12-27 00:00:00
abstract::Overexpression of myeloid cell leukemia-1 (Mcl-1) in cancers correlates with high tumor grade and poor survival. Additionally, Mcl-1 drives intrinsic and acquired resistance to many cancer therapeutics, including B cell lymphoma 2 family inhibitors, proteasome inhibitors, and antitubulins. Therefore, Mcl-1 inhibition ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b01991
更新日期:2019-04-25 00:00:00
abstract::Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transa...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm4019178
更新日期:2014-02-27 00:00:00
abstract::The E and Z isomers of 2-[2-(3-chlorophenyl)-1-phenyl-1-propenyl]pyridine (2a,b) and 2-[2-(3-chlorophenyl)-1-(4-hydroxyphenyl)-1-propenyl]pyridine (4a,b) were synthesized and separated as possible metabolites of 1-(3-chlorophenyl)-1-methyl-2-phenyl-2-(2-pyridine)ethanol (1a). Following administration of 1a to rats, a ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00200a017
更新日期:1978-02-01 00:00:00
abstract::The phenolic "A-ring" of natural and synthetic estrogen receptor (ER) ligands was effectively replaced by a planar six-member ring formed through an intramolecular hydrogen bond within a salicylaldoxime. Thus, oxime 1, a structural analogue of a triarylethylene estrogen, showed a significant binding affinity for the E...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010948j
更新日期:2001-11-22 00:00:00
abstract::A new goup of acridone derivatives, obtained by reaction of acridone-4-carboxylic acid derivatives with aromatic amines, was tested to determine the inhibitory properties toward the NS3 helicase of hepatitis C virus (HCV). Six compounds inhibited the NS3 helicase at low concentrations (IC(50) from 1.5 to 20 microM). T...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm901741p
更新日期:2010-04-22 00:00:00
abstract::The specificity of nucleic acids' binders is crucial for developing this kind of drug, especially for novel G-quadruplexes' binders. Quindoline derivatives have been developed as G-quadruplex stabilizers with good interactive activities. In order to improve the selectivity and binding affinity of quindoline derivative...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00016
更新日期:2017-07-13 00:00:00
abstract::The present study describes a novel in vitro platform for physicochemical profiling of compounds, based on their impact on the air/water interfacial tension. Interfacial partitioning coefficient, cross-sectional area, and critical micelle concentration were derived from the Gibbs adsorption isotherms recorded for 76 s...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0309001
更新日期:2004-03-25 00:00:00
abstract::Inhibitor of secreted frizzled related protein-1 (sFRP-1) would be a novel potential osteogenic agent, since loss of sFRP-1 affects osteoblast proliferation, differentiation, and activity, resulting in improved bone mineral density, quality, and strength. We have identified small molecule diarylsulfone sulfonamide der...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm801069w
更新日期:2008-12-25 00:00:00
abstract::The possibility that catecholamines can be oxidized via aberrant pathways in vivo is open to question, but in vitro oxidation via aerobic manipulations is established. Assuming oxidation does occur, we have examined quantitatively the fast chemical reactions of the initial oxidation products, the o-quinones. The natur...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00223a008
更新日期:1976-01-01 00:00:00
abstract::The synthesis of a new class of multisubstrate adduct inhibitors of polyamine biosynthesis has been investigated. The first target compound, designed to inhibit spermidine synthase, was obtained and proved to be a very potent inhibitor of that enzyme. Two synthetic routes to effect the coupling of the polyamine spermi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00014a023
更新日期:1995-07-07 00:00:00
abstract::Establishing quantitative relationships between molecular structure and broad biological effects has been a long-standing goal in drug discovery. Evaluation of the capacity of molecules to modulate protein functions is a prerequisite for understanding the relationship between molecular structure and in vivo biological...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050494g
更新日期:2005-11-03 00:00:00
abstract::Natural products (NPs) are a rich source of novel compound classes and new drugs. In the present study we have used the chemical space navigation tool ChemGPS-NP to evaluate the chemical space occupancy by NPs and bioactive medicinal chemistry compounds from the database WOMBAT. The two sets differ notably in coverage...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm801514w
更新日期:2009-04-09 00:00:00
abstract::A series of 42 6-arylpyrrolo[2,1-d][1,5]benzothiazepines, which we have recently described as selective ligands of the mitochondrial benzodiazepine receptor (MBR) (Fiorini I.; et al. J. Med. Chem. 1994, 37, 1427-1438), have been investigated using the comparative molecular field analysis (CoMFA) approach. The resultin...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00050a007
更新日期:1994-11-25 00:00:00
abstract::Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00401a014
更新日期:1988-06-01 00:00:00
abstract::Homologous recombination repair (HRR), a crucial approach in DNA damage repair, is an attractive target in cancer therapy and drug design. The Bloom syndrome protein (BLM) is a 3'-5' DNA helicase that performs an important role in HRR regulation. However, limited studies about BLM inhibitors and their biological effec...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b00083
更新日期:2019-03-28 00:00:00
abstract::We explore the significance of pi-cation interactions in the binding of ligands to nicotinic acetylcholine receptors. Specifically, the Austin method of semiempirical molecular orbital theory is utilized to estimate the interaction of aromatic amino acid side chains with the cation-containing heterocyclic ring fragmen...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm990093z
更新日期:1999-08-12 00:00:00
abstract::Analogues of luliberin containing an alpha-azaamino acid in position 6, 9, or 10 (I--XIV) have been synthesized by the solution method of peptide synthesis. Two nonaza analogues, [D-Phe6]- and [D-Ser(But)6,des-Gly-NH2(10),Pro-ethylamide9]luliberin, were also synthesized for comparison. The ovulation-inducing activity ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00208a004
更新日期:1978-10-01 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::A new series of calcium channel agonists structurally related to Bay K8644, containing NO donor furoxans and the related furazans unable to release NO, is described. The racemic mixtures were studied for their action on L-type Ca(2+) channels expressed in cultured rat insulinoma RINm5F cells. All the products proved t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm031109v
更新日期:2004-05-06 00:00:00
abstract::The nortropane cocaine analogue, 2beta-carbomethoxy-3beta-[4'-((Z)-2-iodoethenyl)phenyl]nortropane (ZIENT), is a high affinity, selective serotonin transporter (SERT) ligand that has shown promise as a SERT imaging agent for single photon computed tomography (SPECT) when labeled with I-123. Synthesis of the labeling p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm050799v
更新日期:2006-02-09 00:00:00
abstract::n-Octyl, n-dodecyl, and n-hexadecyl alpha- and gamma-esters of methotrexate (MTX) were compared with the previously described alpha- and gamma-n-butyl esters and with MTX as inhibitors of dihydrofolate reductase (DHFR) and human leukemic lymphoblasts (CEM cells) in culture. The overall order of activity in both test s...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00371a009
更新日期:1984-05-01 00:00:00
abstract::The variation in amino acid sequence within sets of peptides is described by three principal properties, z1, z2, and z3, per varied amino acid position. These principal properties are derived from a principal components analysis of a matrix of 29 physicochemical variables for the 20 coded (in mRNA) amino acids. The sc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00390a003
更新日期:1987-07-01 00:00:00
abstract::Targeting KRAS-PDEδ protein-protein interactions with small molecules represents a promising opportunity for developing novel antitumor agents. However, current KRAS-PDEδ inhibitors are limited by poor cellular antitumor potency and the druggability of the target remains to be validated by new inhibitors. To tackle th...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b00057
更新日期:2018-03-22 00:00:00