The role of ligand efficiency metrics in drug discovery

The judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates

Cement leakage causes potential thermal injury in vertebroplasty

<p>Abstract</p> <p>Background</p> <p>Percutaneous vertebroplasty by injecting PMMA bone cement into the fractured vertebrae has been widely accepted in treatment of spinal compression fracture. However, the exothermic polymerization of bone cement may cause osseous or neural tissue injury. This study is thus designed to evaluate the potential risk of thermal damage in percutaneous vertebroplasty.</p> <p>Method</p> <p>Twelve porcine vertebrae were immersed in 37°C saline for the experiment. In the first stage of the study, vertebroplasty without cement leakage (control group, n = 6) was simulated. The anterior cortex, foramen, posterior cortex and the center of the vertebral body were selected for temperature measurement. Parameters including peak temperature and duration above 45°C were recorded. In the second stage, a model (n = 6) simulating bone cement leaking into the spinal canal was designed. The methods for temperature measurement were identical to those used in the first stage.</p> <p>Results</p> <p>In Stage 1 of the study (vertebroplasty of the porcine vertebral body in the absence of cement leakage), the average maximal temperature at the anterior cortex was 42.4 ± 2.2°C; at the neural foramen 39.5 ± 2.1°C; at the posterior cortex 40.0 ± 2.5°C and at the vertebral center, 68.1 ± 3.4°C. The average time interval above 45°C was 0 seconds at the anterior cortex; at the neural foramen, 0 seconds; at the posterior cortex, 0 seconds and at the vertebral center, 223 seconds. Thus, except at the core of the bone cement, temperatures around the vertebral body did not exceed 45°C. In Stage 2 of the study (cement leakage model), the average maximal temperature at the anterior cortex was 42.7 ± 2.4°C; at the neural foramen, 41.1 ± 0.4°C; at the posterior cortex, 59.1 ± 7.6°C and at the vertebral center, 77.3 ± 5.7°C. The average time interval above 45°C at the anterior cortex was 0 seconds; at the neural foramen, 0 seconds; at the posterior cortex, 329.3 seconds and at the vertebral center, 393.2 seconds. Based on these results, temperatures exceeded 45°C at the posterior cortex and at the vertebral center.</p> <p>Conclusions</p> <p>The results indicated that, for bone cement confined within the vertebra, curing temperatures do not directly cause thermal injury to the nearby soft tissue. If bone cement leaks into the spinal canal, the exothermic reaction at the posterior cortex might result in thermal injury to the neural tissue.</p

Search for Nucleon Decay with Final States l+ eta, nubar eta, and nubar pi+,0 Using Soudan 2

We have searched for nucleon decay into five two-body final states using a 4.4 kiloton-year fiducial exposure of the Soudan 2 iron tracking calorimeter. For proton decay into the fully visible final states mu+ eta and e+ eta, we observe zero and one event, respectively, that satisfy our search criteria for nucleon decay. The lifetime lower limits (tau/B) thus implied are 89 x 10^30 years and 81 x 10^30 years at 90% confidence level. For neutron decay into nubar eta, we obtain the lifetime lower limit 71 x 10^30 years. Limits are also reported for neutron decay into nubar pi0, and for proton decay into nubar pi+.Comment: 24 pages, 9 figures, 3 table

Endothelial Function: The Impact of Objective and Subjective Socioeconomic Status on Flow-Mediated Dilation

Although objective and subjective indicators of socioeconomic status (SES) are linked to cardiovascular disease (CVD), little is known about their relationship to endothelial dysfunction, which often precedes CVD. This study examined how objective and subjective SES relate to brachial artery flow-mediated dilation (FMD). FMD was assessed in 72 healthy adults (mean age 36 years). The MacArthur Scale of Subjective Social Status assessed perceived social standing in the USA (SSS-USA) and local community (SSS-Community). Objective SES measures included income and the Hollingshead Two-Factor Index of Social Position (education, occupation). Adjusted regressions revealed that SSS-Community positively correlated with FMD (p &lt; 0.05) and explained 8% of the variance. No other SES measures were significant for FMD. The association between FMD and SSS-Community remained significant (p &lt; 0.01) after adjustment for objective SES and other covariates. Lower subjective social status in one’s community may be linked to CVD via impaired vasodilation

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference