ライフサイエンスコーパス: hit

1 Those who reported >=1 hit followed by loss of consciousness, compared to those

2 The top 10 hits were validated using an orthogonal assay for endoge

3 initial screen of 2560 molecules yielded 19 hits that effectively disrupted the interaction, and it

4 we adapted an inhibitory avoidance-based "2-hit" rat model of posttraumatic stress disorder (PTSD) a

5 o hits in ~16 000 individuals in 2013 to 223 hits in more than a million individuals in 2020, underst

6 We identified 27 hits that were ranked using a using an algorithm that we

7 at span the entire active site, as well as 3 hits at the dimer interface.

8 e 3-hit algorithm, allowing us to identify 3-hit combinations.

9 r matrix based CPU implementation, for the 3-hit algorithm, allowing us to identify 3-hit combination

10 The 3-hit combinations identified using a training set were ab

11 FRA, the concentration ratio for the top 30 "hits" in each comparison was obtained and then t-tested

12 an glioblastoma (GBM) cells, identifying 467 hits that modify cell growth in the presence of clinical

13 Of the 65 hits initially detected, 24 were excluded based on count

14 Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits

15 rug screens in C. elegans which uncovered 74 hits.

16 A hit-expansion program including design, synthesis, and p

17 dentified phenylisoxazole carboxamide 1 as a hit compound, which inhibited the GATA4-NKX2-5 transcrip

18 and obtained 6 X-ray co-structures, giving a hit rate of 40%.

19 characterized experimentally, resulting in a hit rate of 37% ligands, all of which were agonists.

20 this work, we describe the optimization of a hit compound resulting from the phenotypic screen of a l

21 Here, we present a hit identification approach using AtomNet, the world's f

22 dditional PI3K signaling pathway-activating "hits" (25%).

23 es and propensities to acquire an additional hit.

24 tial to find clinically useful high-affinity hits for the rapid discovery of drugs for targets (e.g.,

25 4 additional families having single allelic hits in MFRP or PRSS56 (7.5%).

26 he optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a he

27 ch has great potential for hit discovery and hit or lead optimization.

28 rformed on dozens of candidate molecules and hit compounds can be conveniently resynthesized on DNA.

29 hysically attacked the snake (with bites and hits), and pulled the victim to safety.

30 ed by phage display and deep sequencing, and hits were characterized by electrophysiological recordin

31 Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, led

32 he primary screen revealed 44 non-antifungal hits were able to act synergistically with fluconazole a

33 Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments wer

34 EC(50)/IC(50) kinetic model fits, as well as hits from high-throughput screening assays.

35 These results suggest that East Asians hit the bamboo ceiling because their low assertiveness i

36 The top association hit was Ncc69 (human NKCC1/2), a conserved ion transport

37 To automate hit identification, we developed a machine-learning mode

38 ucture of H1/PR8 HA in complex with our best hit compound F0045(S) confirmed that it binds to pockets

39 5-fold, while a consensus mutant of the best hits provided a 10-fold improvement.

40 The best hits synthesized were experimentally optimized as a pote

41 leration (adjusted p = 0.0049), time between hits rotational acceleration (adjusted p value 0.0101),

42 were binned into 1,566 different best BLAST hits (BBHs) and counted for each mouse sample.

43 modified approaches of reciprocal best BLAST hits (RBH) and UCLUST.

44 ic effects: if the targets of the drugs both hit disease module, but target separate neighborhoods.

45 ive test, specificity improved to 93.4%, but hit rate decreased to 21.0%.

46 This was followed by hit expansion and analogue synthesis to further improve

47 ed a chemically well-behaved, first-in-class hit with nanomolar anti-RABV potency that blocks RABV G

48 CNVs hitting loss-of-function intolerant genes were associate

49 We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation l

50 In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-

51 These combined hits offer unprecedented structural and reactivity infor

52 dance for in vitro ToxCast assays to confirm hits.

53 n aromatic or heteroaromatic ring-containing hit or lead compounds is one approach toward minimizing

54 otential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correla

55 ting point for a structure-based drug design hit-to-lead program.

56 ics of the common cold and influenza disease hit the human population like clockwork in the winter se

57 niches become increasingly filled, diversity hits a plateau (as predicted by EC).

58 iple myeloma cells in this way take a double hit: immunoproteasome inhibition and doxorubicin-induced

59 We designed a double-hit treatment that allows iNKT cells to escape anergy an

60 In this study, we investigated a "double-hit" approach on primary human endothelial cells primed

61 MYC rearranged and double-hit groups were strongly over-represented in MHG but com

62 f MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lympho

63 Relevant double-hit animal models have provided clues to whether and how

64 y" (i.e., stability) counteracted the double-hit effect on neutrophil TEM.

65 Interestingly, the double-hit-induced TEM increase was not due to decreased endoth

66 The dual hit hypothesis about the pathogenesis of Parkinson disea

67 by surface plasmon resonance, we found eight hits toward the tandem SH3 domain of p47phox (p47phox(SH

68 l high-throughput screening campaign emerged hit 3 among others.

69 its, as well as verify several growth factor hits identified by the siRNA screen.

70 sets with other studies and validated a few hits using an orthogonal imaging technique.

71 Since the COVID-19 pandemic first hit Wuhan, China, in December 2019, scientists have been

72 st competition assay and its application for hit generation of dual TLR7/8 antagonists are reported.

73 ng a using an algorithm that we designed for hit prioritization that we call Hit to Lead Prioritizati

74 this strategy which has great potential for hit discovery and hit or lead optimization.

75 ient sampling of the vast chemical space for hit identification.

76 relationship-driven expansion of a fragment hit led to discovery of dual MNK1 and MNK2 inhibitors ba

77 ructure-based approach, we merged a fragment hit with the previously reported sulfonamide series.

78 ant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), m

79 een was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for

80 erging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent f

81 approaches to elaborate the initial fragment hits, which usually bind with low affinity to their targ

82 Noncovalent fragment hits revealed binding hotspots, while the covalent inhib

83 reover, several studies make use of fragment hits that were previously described in the literature, i

84 scribed, and the development of the fragment hits using a fragment growing strategy was employed, whi

85 o clear boundary between normal and frequent hitting compounds.

86 Furthermore, hits were collectively enriched in genes for which human

87 chromosome 4D identified two candidate gene hits, TraesCS4D02G352200 (TaNox8; an NADPH oxidase) and

88 eded for the accurate identification of gene hits and associated pathways.

89 A second, cooperating genetic hit is often required to push these hyperplastic cells t

90 gets identified as proxies of direct genetic hits are enriched for successful drug targets, as measur

91 strating the conserved role of these genetic hits across species.

92 COVID-19 has been sweeping the globe, hitting the United States particularly hard with a state

93 d analysis still had a significantly greater hit rate than the rule of 5 (47.4% vs. 21.0%, respective

94 nk, we consistently observed lower meta-GWAS hit replication rates and poorer polygenic risk score pr

95 re enriched for coronary artery disease GWAS hits.

96 Few GWAS hits in human genetics for neuropsychiatric disorders to

97 atterns at genomic sites linked to meta-GWAS hits may disrupt established genetic signals in survivor

98 verall limited generalizability of meta-GWAS hits to survivors (n = 4,212; observed-to-expected repli

99 ossible explanation, we found that meta-GWAS hits were less likely to be replicated in survivors who

100 nd candidate genes occurring within the GWAS hits.

101 slating genome-wide association study (GWAS) hits from large meta-analyses (meta-GWAS) in diverse cli

102 e spread of SARS-CoV-2, particularly in hard-hit regions.

103 ally and in many of the U.S. regions hardest hit by the pandemic.

104 peutic avenues that were validated by a high hit rate in a targeted small molecule screen in our iAT2

105 We found validated ligands with a high hit rate of 29% out of those tested, none of them showin

106 e series was the moderate potency of the HTS hits.

107 oal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series "triazolopyridine

108 rting from a high-throughput screening (HTS) hit of our corporate compound library, multiple paramete

109 a phenotypic high-throughput screening (HTS) hit with suboptimal physicochemical properties.

110 d one of the high-throughput screening (HTS) hits, N(2)-(thiophen-3-yl)-N(6)-(2,2,2-trifluoroethyl)-9

111 caused by 88 tropical storms and hurricanes hitting the United States between 1996 and 2016 and show

112 ructure-activity relationships of identified hits led to the first SmSirt2 inhibitors with activity i

113 oughput virtual screening led us to identify hit compound 5, endowed with promising antienzymatic act

114 R based KD determination to rapidly identify hits and their binding poses.

115 The impact hit a carbonate platform and released sulfate aerosols a

116 eened on hMC4R, this bank gave an incredible hit rate of 8%.

117 Starting from an initial hit molecule, we report its divergent optimization towar

118 in, we describe the synthesis of our initial hit TCMDC-135051 (1) and efforts to establish a structur

119 ing wet-laboratory experiments, poor initial hit compounds and the high attrition rates in the (pre-)

120 geminal dimethylindoline core of the initial hit compound to a spiroindoline system significantly imp

121 Compared with the initial hit, 36 showed improved potency in a guanosine 5'-O-[gam

122 SAR studies on the initial hit, compound 4 (IC(50) = 257 nM), resulted in several h

123 their ability to replace OCH as the initial hit, with their lipid chain length being a determinant o

124 ent the chemical optimization of our initial hits, 2-oxo-4-phenyl-N-(4-phenylbutyl)oxazole-3-carboxam

125 y for the target RNA relative to the initial hits, while also having significantly improved drug-like

126 at a given target did not correlate with its hit rate.

127 identified as high-ranking essential kinase hits in the HNSCC cell lines.

128 against MRSA (USA300) revealed several lead hits with improved activity over methicillin.

129 compounds were identified as validated lead-hits, and four were prioritized for further study (endos

130 Pupil diameter determines how much light hits the retina and, thus, how much information is avail

131 ng account.SIGNIFICANCE STATEMENT When light hits the retina, the pupil reflexively constricts.

132 Although most targets favored lipophilic hits, the average clogP of hits at a given target did no

133 Thirty-three of these lncRNA hits sensitize cells to radiation, and based on their ex

134 mparing the samples, the counts of localized hits matching the domains of interest were normalized to

135 The exceptionally low hit rate observed here suggests that PrP is a difficult

136 llation proximity assay (SPA) HTS at a lower hit rate and with a significantly reduced cost per well

137 found the anticancer drug sorafenib as major hit that effectively kills MRSA strains.

138 The major hit from our gain-of-function screen is the apical polar

139 through automated screening techniques; many hits and some new mechanisms involved in axonal regenera

140 the high cost of conference attendance might hit students and early-career researchers the hardest.

141 brary to identify a promising small molecule hit (GY1-22) against the interacting pocket in the DNAJA

142 ghput screen and discovered a small molecule hit that is highly selective for ERAP1.

143 to identify EC(50) values of small-molecule hits, as well as verify several growth factor hits ident

144 use gene knockouts identified 140 monogenic 'hits', of which most had no previous immunologic associa

145 ncers are estimated to require three or more hits.

146 Primary screens identified over tenfold more hits than screening wild-type Mtb alone, with chemical-g

147 arated in time and space, supporting a multi-hit model in which emergence of autoreactive T cells is

148 whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting.

149 of carcinogenic genes with mutations (multi-hit combinations), which could suggest a likely cause fo

150 an algorithm that identified a set of multi-hit combinations that differentiate between tumor and no

151 ons in tumor and normal samples in the multi-hit gene combinations can suggest potential driver mutat

152 ion and poor outcomes were specific to multi-hit patients only.

153 TP53 multi-hit state predicted risk of death and leukemic transform

154 ic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting.

155 combinations of multiple genetic mutations (hits).

156 as a starting point for the synthesis of new hits against Trypanosoma brucei, the causative agent of

157 were assigned and used to categorize the NMR hits into different classes.

158 etitive displacement assay to identify novel hit matter.

159 We explore the numerous hit molecules beginning to emerge from high-content/high

160 Here, semisynthetic analogues of hit were designed, synthetized, and tested against colis

161 Target analysis of hit compounds revealed androgen signaling as a key modul

162 nalyzed in more depth, giving 75 examples of hit to lead development.

163 tion assay, we obtained only a low number of hit compounds.

164 The AMI-MS assay identified 86% of hits previously identified, with a pIC(50) >= 5.0, in a

165 We assessed the activity of hits against human NMT1 and NMT2 and discarded compounds

166 nologies result in an extensive attrition of hits during validation experiments.

167 avored lipophilic hits, the average clogP of hits at a given target did not correlate with its hit ra

168 usands of compounds and identified dozens of hits that caused paradoxical excitation.

169 by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecule

170 ithm scales exponentially with the number of hits, making it impractical for identifying combinations

171 tion strategies, and molecular properties of hits and leads are presented in the hope of informing be

172 ing of the library beads allowed recovery of hits improved in Kd over wild-type ZIgE by up to 3.5-fol

173 From this set of hits, a cluster of diaminopurine-derived compounds was i

174 e interaction, and it was confirmed that one hit disrupted VPS34 Complex I formation and inhibited au

175 duration of design cycles needed to optimize hit or lead compounds into high-quality chemical probes

176 In addition, our hit compounds show good activity against the liver stage

177 We then combined features from our hits with those of known inhibitors to create a 'hybrid'

178 The approach is effective, with an overall hit rate of ~30% at 30 muM and discovery of potent compo

179 gely divergent results, with few overlapping hits across different studies.

180 Positive hits from this initial screen were then further narrowed

181 Positive hits were assessed for AR subtype selectivity through cA

182 ng, and further characterization of positive hits (that is, IC(50) and K(i) ), as well as inhibition-

183 Among these positive hits, Est WY was identified as a novel esterase with hig

184 A potent hit compound was discovered containing a (R)-N-(piperidi

185 l product jawsamycin (FR-900848) as a potent hit.

186 inal chemistry optimization, the most potent hit has IC(50) 280 nM, corresponding to K (i) of 173 nM.

187 polyketides Aureothin/Neoaureothin as potent hits by anti-HIV screening of an extensive natural compo

188 al screen advanced 38 compounds as potential hits, of which, four compounds enhanced endothelial barr

189 lar modeling, is critical in the preclinical hit and lead identification process.

190 maker accumulates evidence until the process hits either an upper or lower stopping boundary and then

191 A benzamide pyridine hit derived from a focused screen was successfully devel

192 tructure-guided optimization of the pyridone hit 3 using this biochemical assay in combination with c

193 support a facile method for affinity-ranking hits.

194 hanges), and 13 fall within loci recurrently hit by copy number variants.

195 ificance; however, 16 genes were recurrently hit by protein-truncating DNMs, corresponding to a 3.15-

196 ants and thus were termed as "repositionable hits".

197 e compound screening campaign and a rigorous hit-to-lead flowchart combining biochemical and biophysi

198 ts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound.

199 Evaluation of the top scoring hit, Trichostatin A (TSA), demonstrated utrophin upregul

200 From 366 screen hits we further validated the antiplasmid activity of ka

201 Among ~550 identified screen hits is MLX, a basic helix-loop-helix leucine-zipper tra

202 ntify that published synthetic lethal screen hits significantly overlap at the pathway rather than ge

203 Intersection of screen hits obtained from two cell lines and orthogonal approac

204 We validated screen hits by demonstrating that adoptive transfer of CD8(+) T

205 ver, treatment of parasites with a screening hit from the malaria box compound collection, MMV007839,

206 atives were synthesized based on a screening hit.

207 ough optimization of a 6-azaindole screening hit.

208 g of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled

209 A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was s

210 rting from an in-house proprietary screening hit followed by structure-based rational design, we have

211 Starting from a non-selective screening hit, we have achieved the goal of discovering molecules

212 al optimization of high-throughput screening hit 8 to a potent, metabolically stable, and orally bioa

213 (TMPA), and three high-throughput screening hit derivatives.

214 viously found in a high-throughput screening hit that binds in a nonconserved allosteric site.

215 A high-throughput screening hit was modified at three different substituents to opti

216 he lesion location, indicating that a second hit to the same circuit might be beneficial.

217 usative role for plasmin (ogen) as a "second hit" in kidney disease progression has yet to have been

218 ent regulatory genes that serve as a "second hit," leading to uncontrolled complement activation and

219 intestinal Chlamydia might induce the second hit to promote genital tract pathology, and we are now p

220 arallel evolution, including distinct second hits in SMARCA4, a putative predisposition gene for neur

221 Selected hits were validated by RT-qPCR and in CRISPRi competitio

222 Bioavailability and efficacy of selected hits were assessed in a T. cruzi mouse model, where 6a a

223 The seminal hit molecule was discovered by virtual screening and con

224 Among the most sensitizing hits were proteins involved in mitochondrial translation

225 vasion screen, which identified two separate hits, IMPAD1 and KDELR2, as robust, independent drivers

226 sulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities aga

227 Several hits were validated using a DNAJA1 inhibitor (116-9e) in

228 Nevertheless, several hits were identified as Lessonia exclusive or more remar

229 se assays to experimentally validate several hits from our primary data, as well as variants for whic

230 We also observed a significant hit in PTPN22 and the GWAS results correlated with the g

231 ad of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogr

232 nd estimated viral loads based on the single-hit Poisson model were compared, and a hybrid Poisson di

233 The strongest hits were components of the ESCRT complexes.

234 is linked to UBQLN2 function, the strongest hits were the ubiquitin ligase TRIM32 and two retroeleme

235 Subsequent hit-to-lead optimization, using cocrystal structures of

236 reward structure (ratio of points for target hits and misses) for different exploitation horizons (i.

237 The hit-to-lead optimization led to the discovery of a novel

238 a valuable technology for democratizing the hit discovery process.

239 We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5-a]pyrim

240 We discovered the hit compound NR-160 by investigating the inhibition of r

241 In mice, the hit compound increased body temperature, UCP1 protein le

242 pecific protein domains and to normalize the hit-counts based on the domain length.

243 Counterscreening of the hit compounds provided an assessment of their selectivit

244 ness criteria (mainly MW, clogP) reduces the hit rates of attractive chemical starting points in subs

245 At the same specificity, the hit rate for trend-based analysis was significantly grea

246 The hits from HTS were further screened for their AChE inhib

247 The hits from this unbiased screen and the mechanistic valid

248 The hits identified in this analysis included specific genes

249 Among the hits, domperidone emerged as an effective corrector that

250 A methylation status in VSMCs, and among the hits, we selected miR-128.

251 We have further compared the hits found from our proteomic data sets with other studi

252 s spectrometry followed by validation of the hits by biochemical and functional analyses.

253 -based virtual screening, the quality of the hits improves with the number of compounds screened(2).

254 We used four of the hits to program hPSCs into neurons, fibroblasts, oligode

255 of 5 to allow meaningful comparison of the "hit rate," or the proportion of glaucoma eyes categorize

256 These hits included expected PI3K interactors, such as the pla

257 n adult and pediatric gliomas, nine of these hits are prioritized as lncRNA Glioma Radiation Sensitiz

258 fied a number of notable features that these hits tend to have in common, including preferences in bu

259 To validate these hits from the screen, we developed patient-derived xenog

260 culosis identified 1, a thioalkylbenzoxazole hit.

261 well as physicochemical properties for those hits were evaluated.

262 compounds was conducted, resulting in three hit compounds with the desired selectivity profile.

263 work demonstrates a powerful new approach to hit-finding.

264 Small structure modifications to hit or lead compounds can have meaningful impacts on pha

265 ceutical companies due to their potential to hit currently "undruggable" targets.

266 We further characterized a top hit from the screen, progenitor renewal associated non-c

267 e for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-ph

268 teomic analysis identified Rab7-S72 as a top hit.

269 Unexpectedly, one top hit was Traf3, a negative regulator of NF-kappaB signali

270 16 within the Class II HLA region as the top hit (P = 2 x 10(-14)); this was in linkage disequilibriu

271 The top hit from these screens was GSG2 (also known as Haspin),

272 The top hit of the screen is the cytosolic Malic Enzyme (ME1), t

273 encoding the phage receptor(s) were the top hit(s) in the analyses of the successful screens.

274 , or the histone acetyltransferase KAT5, top hits from our screens, robustly reverses the PARPi sensi

275 One of the top hits from the screen was RAP80, a protein that recruits

276 Among the top hits was MAX, the obligate heterodimerization partner fo

277 Unexpectedly, one of the top 'hits' was a GSK3 inhibitor, an agonist of Wnt signaling.

278 by immunohistochemistry and double or triple hit status was determined by cytogenetics.

279 er BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed

280 Surprisingly, in contrast to Knudsen's two hit hypothesis, the p.S745L somatic mutation was always

281 Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 12

282 l dominant tumor syndrome resulting from two hits to the same allele of PLCD1 tumor suppressor gene.

283 erized detailed mechanistic functions of two hits.

284 To identify combinations of greater than two hits, we used a compressed binary matrix representation,

285 or identifying combinations of more than two hits.

286 We previously proposed a two-hit model in which the mouse gastrointestinal Chlamydia

287 e presence of amyloid, consistent with a two-hit model of AD on cognition.

288 D-like aberrations in mice using a novel two-hit model.

289 st a pathologic role of monocytes in the two-hit (immune plus neonatal HI) model of neurodevelopmenta

290 We demonstrate that upon hitting a host cell, motile Pseudomonas aeruginosa induc

291 Among the top validated hits are two interacting components of the polycomb repr

292 Significant, and independently validated, hits demonstrated the importance of multiple protein fam

293 Among validating hits are genes coding for the N(6)-methyladenosine (m(6)

294 ble functional group can be found in various hit-to-lead and lead optimization studies in early stage

295 r subpopulations can promote metastases via "hit-and-run" commensal interactions.

296 The patient was hit by several lead hunting pellets in the chest, abdome

297 context of DNA-encoded libraries, for which hit validation procedures need to be performed on dozens

298 CI: 0.0, 3.3) and reporting a partner would hit her if she asked him to wear a condom (indirect effe

299 A majority of targets yielded hits with higher clogP, molecular weight, and more basic

300 studies of depression, from identifying zero hits in ~16 000 individuals in 2013 to 223 hits in more