Abstract：
:In the past 15 years, fragment-based lead discovery (FBLD) has been adopted widely throughout academia and industry. The approach entails discovering very small molecular fragments and growing, merging, or linking them to produce drug leads. Because the affinities of the initial fragments are often low, detection methods are pushed to their limits, leading to a variety of artifacts, false positives, and false negatives that too often go unrecognized. This Digest discusses some of these problems and offers suggestions to avoid them. Although the primary focus is on FBLD, many of the lessons also apply to more established approaches such as high-throughput screening.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Davis BJ,Erlanson DAdoi
10.1016/j.bmcl.2013.03.028subject
Has Abstractpub_date
2013-05-15 00:00:00pages
2844-52issue
10eissn
0960-894Xissn
1464-3405pii
S0960-894X(13)00344-2journal_volume
23pub_type
杂志文章abstract：:We herein report the discovery of a new γ-secretase modulator class with an aminothiazole core starting from a HTS hit (3). Synthesis and SAR of this series are discussed. These novel compounds demonstrate moderate to good in vitro potency in inhibiting amyloid beta (Aβ) peptide production. Overall γ-secretase is not ...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2011.08.060
更新日期：2011-11-01 00:00:00
abstract：:The objective of this Letter is to report the first (to our knowledge) in vivo proof of concept for a sulfenamide prodrug to orally deliver a poorly soluble drug containing a weakly-acidic NH-acid from a conventional solid dosage formulation. This proof of concept was established using BMS-708163 (1), a gamma secretas...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2019.126856
更新日期：2020-02-01 00:00:00
abstract：:A series of [4,6-(substituted aryl)-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetic acid (4a-r) has been synthesized by the base catalyzed condensation of beta-aroylpropionic acid, thiourea with aldehyde in ethanol. Structures of the new compound were established on the basis of (1)H NMR and IR spectral data. Anti-...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2004.01.039
更新日期：2004-04-05 00:00:00
abstract：:Cancer cells isolated from two patients with malignant non-Hodgkin B-cell lymphomas that became resistant to chemotherapy during clinical treatment were made ≥fourfold resistant in culture to anticancer drugs, that is cisplatin, etoposide, methotrexate and bortezomib. Because most resistant lines showed significantly ...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2012.08.091
更新日期：2012-11-01 00:00:00
abstract：:Benz[b]oxepines 4a-g and 12-oxobenzo[c]phenanthridines 5a-d were designed and synthesized as constrained forms of 3-arylisoquinolines through an intramolecular radical cyclization reaction. Radical cyclization of O-vinyl compounds preferentially led to the 7-endo-trig cyclization pathway to the benz[b]oxepines and 12-...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2009.03.058
更新日期：2009-05-01 00:00:00
abstract：:Toll-like receptors (TLRs) are a type of pattern recognition receptors (PRRs), which are activated by recognizing pathogen-associated molecular patterns (PAMPs). The activation of TLRs initiates innate immune responses and subsequently leads to adaptive immune responses. TLR agonists are effective immuomodulators in v...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2019.126840
更新日期：2020-02-01 00:00:00
abstract：:Casein kinase 2 catalytic subunit (CK2α) is classified into two subtypes CK2α1 and CK2α2. CK2α1 is a drug discovery target, whereas CK2α2 is an off-target of CK2α1 inhibitors. High amino acid sequence homology between these subtypes hampers efforts to produce ATP competitive inhibitors that are highly selective to CK2...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2019.126837
更新日期：2020-01-15 00:00:00
abstract：:A series of 4'-hydroxyphenyl-aryl-carbaldehyde oximes (5b) was prepared and found to have high affinity (4nM) and modest selectivity (39-fold) for estrogen receptor-beta (ERbeta). Substitution of one of the core rings of the scaffold based around these novel ligands further expanded our knowledge in the quest toward a...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2006.11.066
更新日期：2007-02-15 00:00:00
abstract：:Two novel compounds with mannose-derived structure, bearing a tetrazole (compound 3) and a sulfone group (compound 4) in terminal position, have been prepared from methyl α-d-mannopyranoside in reduced number of steps. The angiogenic activity of 3 and 4 has been screened using the chick chorioallantoic membrane (CAM) ...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2015.11.059
更新日期：2016-01-15 00:00:00
abstract：:Protein-protein interactions (PPIs) present a formidable challenge to medicinal chemistry. The extended and open nature of many binding sites at protein interfaces has made it difficult to find useful chemical matter by traditional screening methods using standard screening libraries. This Digest focuses on the progre...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章,评审
doi：10.1016/j.bmcl.2015.04.089
更新日期：2015-06-15 00:00:00
abstract：:4,4-dimethyl-5 alpha-cholesta-8,14,24-trien-3 beta-ol, a sterol of current biological interest, has been synthesized in six steps from 3 beta-acetoxy-4,4-dimethyl-5 alpha-cholest-8(14)-en-15-one. ...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/s0960-894x(98)00016-x
更新日期：1998-02-03 00:00:00
abstract：:Lactimidomycin (LTM, 1), iso-migrastatin (iso-MGS, 2) and migrastatin (MGS, 3) are macrolide antitumor antibiotics differing in macrolide ring size but all bearing a glutarimide side chain. To further develop these natural products and related analogs as drug candidates we have produced and evaluated the biological ac...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2008.07.072
更新日期：2008-11-15 00:00:00
abstract：:The identification of a novel hit compound inhibitor of the protein-protein interaction between the influenza RNA-polymerase PA and PB1 subunits has been accomplished by means of high-throughput screening. A small family of structurally related molecules has been synthesized and biologically evaluated with most of the...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2013.08.048
更新日期：2013-10-15 00:00:00
abstract：:A series of potent arenavirus inhibitors sharing a benzimidazole core were previously reported by our group. SAR studies were expanded beyond the previous analysis, which involved the attached phenyl rings and methylamino linker portion, to include modifications focused on the benzimidazole core. These changes include...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2012.11.093
更新日期：2013-02-01 00:00:00
abstract：:Androgen receptor activity drives incurable castrate-resistant prostate cancer. All approved antiandrogens inhibit androgen receptor-driven transcription, and in addition the second-generation antiandrogen MDV3100 inhibits ligand-activated androgen receptor nuclear translocation, via an unknown mechanism. Here, we rep...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2011.12.141
更新日期：2012-03-01 00:00:00
abstract：:The peptidomimetic, LLP2A, is a specific, high-affinity ligand for α4β1 integrin receptors. Previously, several PEGylated LLP2A conjugates were evaluated in vivo as imaging agents for the detection of lymphoma, leukemia, multiple myeloma and melanoma tumours via NIR-fluorescence, 111In-SPECT, and 64Cu- and 68Ga-PET im...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2016.08.011
更新日期：2016-10-15 00:00:00
abstract：:Compound DNSTT-Cu2+, a novel chelate of Cu2+ with DOTA conjugated to a fluorescent dansyl fragment, is developed for imaging cell apoptosis. Apoptotic U-87MG cells could be selectively visualized by the fluorescence of DNSTT-Cu2+ from cytoplasm of cells, confirmed by the fluorescence of apoptosis cells co-labeled with...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2016.09.057
更新日期：2016-11-15 00:00:00
abstract：:As the best-characterized ubiquitin-like protein (UBL), small ubiquitin-related modifier (SUMO) was found to conjugate with a number of proteins to regulate cellular functions including transcription, signal transduction, and cell cycle. While E1, E2 and E3 ligases are responsible for the forward SUMOylation reaction,...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2011.08.101
更新日期：2011-11-01 00:00:00
abstract：:Inhibition of the aspartyl protease renin is considered as an efficient approach for treating hypertension. Lately, we described the discovery of a novel class of direct renin inhibitors which comprised a pyrrolidine scaffold (e.g., 2). Based on the X-ray structure of the lead compound 2 bound to renin we predicted th...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2015.02.040
更新日期：2015-04-15 00:00:00
abstract：:In an effort to better understand the conformational preferences that inform the biological activity of naltrexone and related naltrexol derivatives, a new synthesis of the restricted analog 3-OBn-6β,14-epoxymorphinan 4 is described. 4 was synthesized starting from naltrexone in 50% overall yield, proceeding through t...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2012.06.056
更新日期：2012-11-15 00:00:00
abstract：:Seedlings of natural crops are valuable sources of pharmacologically active phytochemicals. In this study, we aimed to identify new active secondary metabolites in Avena sativa L. (oat) seedlings. Two new compounds, avenafuranol (1) and diosgenoside (2), along with eight known compounds (3-10) were isolated from the A...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2020.127250
更新日期：2020-07-15 00:00:00
abstract：:A series of regioisomeric bis-fulleropyrrolidines bearing two ammonium groups have been synthesized and their activities against HIV-1 and HIV-2 have been evaluated. Two trans isomers have been endowed with interesting antiviral properties, confirming the importance of the relative positions of the substituent on the ...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2005.05.069
更新日期：2005-08-01 00:00:00
abstract：:High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that led to the identification of ...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2005.04.074
更新日期：2005-07-01 00:00:00
abstract：:A series of potent ALK5 inhibitors were designed using a SBDD approach and subsequently optimized to improve drug likeness. Starting with a 4-substituted quinoline screening hit, SAR was conducted using a ALK5 binding model to understand the binding site and optimize activity. The resulting inhibitors displayed excell...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2017.03.026
更新日期：2017-05-01 00:00:00
abstract：:A series of compounds originally derived from thalidomide were synthesized and evaluated. The most potent compounds in this series, 5HPP-33 and compound 20, inhibited NF-kappaB activation in HeLa cells. Preliminary study indicated that the mechanism of inhibition of NF-kappaB activation is through inhibition of its tr...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2007.01.088
更新日期：2007-11-01 00:00:00
abstract：:An HTS campaign of our corporate compound library resulted in thieno[2,3-b]pyridines derivative hits with mGluR5 negative allosteric modulator effects. During the hit-to-lead development our objective was to improve affinity, and to keep the ligand efficiency values at an acceptable level. After different modification...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2014.06.057
更新日期：2014-08-15 00:00:00
abstract：:Derivatives of a CYP1A2 inhibitor rutaecarpine were synthesized to have potent and selective inhibition of human CYP1 members. Structural modelling shows a good fitting of rutaecarpine with the putative active site of human CYP1A2. Among the derivatives, 10- and 11-methoxyrutaecarpine are the most selective CYP1B1 inh...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/s0960-894x(03)00469-4
更新日期：2003-08-04 00:00:00
abstract：:NAD(P)H-dependent oxidoreductases play important roles in biology. Recently, we reported that the luminescence lifetime of some Tb(3+) complexes is sensitive to NAD(P)H, and we used this phenomenon to detect activities of these enzymes. However, conventional time-resolved luminescence assays are susceptible to static ...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2016.03.038
更新日期：2016-05-01 00:00:00
abstract：:Makomotindoline (1) was isolated from Makomotake, Zizania latifolia infected with Ustilago esculenta. The structure was determined by the interpretation of spectroscopic data and synthesis. Makomotindoline (1), its l-Glc isomer (2) and its aglycon (3) were synthesized and their effects on rat glioma cells showed adver...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2012.05.021
更新日期：2012-07-01 00:00:00
abstract：:To make full use both of optical properties of quantum dots (QDs) and of specific interactions between aptamers and their ligands of interest, we employed QD-conjugated RNA aptamer interactions with histidine tag. QDs offer revolutionary fluorescence performance due to their long-term photostability, brilliant colors,...
journal_title：Bioorganic & medicinal chemistry letters
pub_type： 杂志文章
doi：10.1016/j.bmcl.2010.04.040
更新日期：2010-06-01 00:00:00
