Methyl effects on protein-ligand binding Leung, Cheryl S; Leung, Siegfried S F; Tirado-Rives, Julian ...
Journal of medicinal chemistry,
05/2012, Letnik:
55, Številka:
9
Journal Article
Recenzirano
Odprti dostop
The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is ...found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in depth to elucidate any unusual aspects of the protein-ligand binding, distribution of water molecules, and changes in conformational energetics. The analyses include Monte Carlo/free-energy perturbation (MC/FEP) calculations for methyl replacements in inhibitor series for p38α MAP kinase, ACK1, PTP1B, and thrombin. Methyl substitutions ortho to an aryl ring can be particularly effective at improving activity by inducing a propitious conformational change. The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein.
We investigate the relationship between passive permeability and molecular size, in the context of solubility-diffusion theory, using a diverse compound set with molecular weights ranging from 151 to ...828, which have all been characterized in a consistent manner using the RRCK cell monolayer assay. Computationally, each compound was subjected to extensive conformational search and physics-based permeability prediction, and multiple linear regression analyses were subsequently performed to determine, empirically, the relative contributions of hydrophobicity and molecular size to passive permeation in the RRCK assay. Additional analyses of Log D and PAMPA data suggest that these measurements are not size selective, a possible reason for their sometimes weak correlation with cell-based permeability.
To test the hypothesis that prognostication of treatment outcome is feasible by biomarker response at midcourse of chemoradiotherapy (CRT)/radiotherapy (RT), with respect to the plasma load of ...Epstein–Barr viral (EBV) DNA in nasopharyngeal carcinoma (NPC).
One hundred seven patients with stage IIB–IV NPC were prospectively studied. Plasma EBV DNA load was measured by quantitative PCR before therapy (pre-DNA), at completion of 4 weeks of CRT/RT (mid-DNA), and within 3 months of completion of therapy (post-DNA). The end points are post-DNA load, a recognized surrogate of survival, and clinical outcome.
Ninety-three percent of patients had detectable EBV DNA before therapy (median load = 972 copies/ml). EBV DNA became undetectable in 55 (51%) patients at the end of week 4 of therapy. Detectable mid-DNA was associated with worse clinical outcome (median follow-up time, 6.2 years), for distant failure hazard ratio (HR) 12.02, 95% confidence interval (CI) 2.78–51.93; P < 0.0001, progression-free survival (PFS; HR 4.05, 95% CI 1.89–8.67, P < 0.0001), and overall survival (OS; HR 3.29, 95% CI 1.37–7.90, P = 0.0077). Seventy-four percent of all failures were associated with detectable mid-DNA, whereas 34% of all failures were associated with detectable post-DNA. Stratification by tumor stage (IIB, III, IV) has no significant prognostic effect.
Unfavorable EBV DNA response at midcourse of RT/CRT is an adverse prognosticator for treatment outcome, is linked to majority of all failures, and discriminates outcome better than tumor stage. The data could provide a basis for trial design that addresses alteration of therapy intensity during the latter phase of CRT, and adjuvant therapy. Validation studies are awaited.
Drug design efforts are turning to a new generation of therapeutic targets, such as protein-protein interactions (PPIs), that had previously been considered "undruggable" by typical small molecules. ...There is an emerging view that accessing these targets will require molecules that are larger and more complex than typical small molecule drugs. Here, we present a methodology for the discovery of geometrically diverse, membrane permeable cyclic peptide scaffolds based on the synthesis and permeability screening of a combinatorial library, followed by deconvolution of membrane-permeable scaffolds to identify cyclic peptides with good to excellent passive cell permeabilities. We use a combination of experimental and computational approaches to investigate structure-permeability relationships in one of these scaffolds, and uncover structural and conformational factors that govern passive membrane diffusion in a related set of cyclic peptide diastereomers. Further, we investigate the dependency of permeability on side-chain identity of one of these scaffolds through single-point diversifications to show the adaptability of these scaffolds toward development of permeability-biased libraries suitable for bioactivity screens. Overall, our results demonstrate that many novel, cell permeable scaffolds exist beyond those found in extant natural products, and that such scaffolds can be rapidly identified using a combination of synthesis and deconvolution which can, in principle, be applied to any type of macrocyclic template.
Nasopharyngeal carcinoma (NPC) is highly sensitive to both radiotherapy (RT) and chemotherapy. This randomized phase III trial compared concurrent cisplatin-RT (CRT) with RT alone in patients with ...locoregionally advanced NPC.
Patients with Ho's N2 or N3 stage or N1 stage with nodal size > or = 4 cm were randomized to receive cisplatin 40 mg/m(2) weekly up to 8 weeks concurrently with radical RT (CRT) or RT alone. The primary end point was progression-free survival (PFS).
Three hundred fifty eligible patients were randomized. Baseline patient characteristics were comparable in both arms. There were significantly more toxicities, including mucositis, myelosuppression, and weight loss in the CRT arm. There were no treatment-related deaths in the CRT arm, and one patient died during treatment in the RT-alone arm. At a median follow-up of 2.71 years, the 2-year PFS was 76% in the CRT arm and 69% in the RT-alone arm (P =.10) with a hazards ratio of 1.367 (95% confidence interval CI, 0.93 to 2.00). The treatment effect had a significant covariate interaction with tumor stage, and a subgroup analysis demonstrated a highly significant difference in favor of the CRT arm in Ho's stage T3 (P =.0075) with a hazards ratio of 2.328 (95% CI, 1.26 to 4.28). For T3 stage, the time to first distant failure was statistically significantly different in favor of the CRT arm (P =.016).
Concurrent CRT is well tolerated in patients with advanced NPC in endemic areas. Although PFS was not significantly different between the concurrent CRT arm and the RT-alone arm in the overall comparison, PFS was significantly prolonged in patients with advanced tumor and node stages.
There has been an outbreak of the severe acute respiratory syndrome (SARS) worldwide. We report the clinical, laboratory, and radiologic features of 138 cases of suspected SARS during a hospital ...outbreak in Hong Kong.
From March 11 to 25, 2003, all patients with suspected SARS after exposure to an index patient or ward were admitted to the isolation wards of the Prince of Wales Hospital. Their demographic, clinical, laboratory, and radiologic characteristics were analyzed. Clinical end points included the need for intensive care and death. Univariate and multivariate analyses were performed.
There were 66 male patients and 72 female patients in this cohort, 69 of whom were health care workers. The most common symptoms included fever (in 100 percent of the patients); chills, rigors, or both (73.2 percent); and myalgia (60.9 percent). Cough and headache were also reported in more than 50 percent of the patients. Other common findings were lymphopenia (in 69.6 percent), thrombocytopenia (44.8 percent), and elevated lactate dehydrogenase and creatine kinase levels (71.0 percent and 32.1 percent, respectively). Peripheral air-space consolidation was commonly observed on thoracic computed tomographic scanning. A total of 32 patients (23.2 percent) were admitted to the intensive care unit; 5 patients died, all of whom had coexisting conditions. In a multivariate analysis, the independent predictors of an adverse outcome were advanced age (odds ratio per decade of life, 1.80; 95 percent confidence interval, 1.16 to 2.81; P=0.009), a high peak lactate dehydrogenase level (odds ratio per 100 U per liter, 2.09; 95 percent confidence interval, 1.28 to 3.42; P=0.003), and an absolute neutrophil count that exceeded the upper limit of the normal range on presentation (odds ratio, 1.60; 95 percent confidence interval, 1.03 to 2.50; P=0.04).
SARS is a serious respiratory illness that led to significant morbidity and mortality in our cohort.
Early identification and intervention are imperative for suicide prevention. However, at-risk people often neither seek help nor take professional assessment. A tool to automatically assess their ...risk levels in natural settings can increase the opportunity for early intervention.
The aim of this study was to explore whether computerized language analysis methods can be utilized to assess one's suicide risk and emotional distress in Chinese social media.
A Web-based survey of Chinese social media (ie, Weibo) users was conducted to measure their suicide risk factors including suicide probability, Weibo suicide communication (WSC), depression, anxiety, and stress levels. Participants' Weibo posts published in the public domain were also downloaded with their consent. The Weibo posts were parsed and fitted into Simplified Chinese-Linguistic Inquiry and Word Count (SC-LIWC) categories. The associations between SC-LIWC features and the 5 suicide risk factors were examined by logistic regression. Furthermore, the support vector machine (SVM) model was applied based on the language features to automatically classify whether a Weibo user exhibited any of the 5 risk factors.
A total of 974 Weibo users participated in the survey. Those with high suicide probability were marked by a higher usage of pronoun (odds ratio, OR=1.18, P=.001), prepend words (OR=1.49, P=.02), multifunction words (OR=1.12, P=.04), a lower usage of verb (OR=0.78, P<.001), and a greater total word count (OR=1.007, P=.008). Second-person plural was positively associated with severe depression (OR=8.36, P=.01) and stress (OR=11, P=.005), whereas work-related words were negatively associated with WSC (OR=0.71, P=.008), severe depression (OR=0.56, P=.005), and anxiety (OR=0.77, P=.02). Inconsistently, third-person plural was found to be negatively associated with WSC (OR=0.02, P=.047) but positively with severe stress (OR=41.3, P=.04). Achievement-related words were positively associated with depression (OR=1.68, P=.003), whereas health- (OR=2.36, P=.004) and death-related (OR=2.60, P=.01) words positively associated with stress. The machine classifiers did not achieve satisfying performance in the full sample set but could classify high suicide probability (area under the curve, AUC=0.61, P=.04) and severe anxiety (AUC=0.75, P<.001) among those who have exhibited WSC.
SC-LIWC is useful to examine language markers of suicide risk and emotional distress in Chinese social media and can identify characteristics different from previous findings in the English literature. Some findings are leading to new hypotheses for future verification. Machine classifiers based on SC-LIWC features are promising but still require further optimization for application in real life.
The biophysical basis of passive membrane permeability is well-understood, but most methods for predicting membrane permeability in the context of drug design are based on statistical relationships ...that indirectly capture the key physical aspects. Here, we investigate molecular mechanics-based models of passive membrane permeability and evaluate their performance against different types of experimental data, including parallel artificial membrane permeability assays (PAMPA), cell-based assays, in vivo measurements, and other in silico predictions. The experimental data sets we use in these tests are diverse, including peptidomimetics, congeneric series, and diverse FDA approved drugs. The physical models are not specifically trained for any of these data sets; rather, input parameters are based on standard molecular mechanics force fields, such as partial charges, and an implicit solvent model. A systematic approach is taken to analyze the contribution from each component in the physics-based permeability model. A primary factor in determining rates of passive membrane permeation is the conformation-dependent free energy of desolvating the molecule, and this measure alone provides good agreement with experimental permeability measurements in many cases. Other factors that improve agreement with experimental data include deionization and estimates of entropy losses of the ligand and the membrane, which lead to size-dependence of the permeation rate.
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