Modelling the binding mode of macrocycles: Docking and conformational sampling

Drug discovery is increasingly tackling challenging protein binding sites regarding molecular recognition and druggability, including shallow and solvent-exposed protein-protein interaction interfaces. Macrocycles are emerging as promising chemotypes to modulate such sites. Despite their chemical complexity, macrocycles comprise important drugs and offer advantages compared to non-cyclic analogs, hence the recent impetus in the medicinal chemistry of macrocycles. Elaboration of macrocycles, or constituent fragments, can strongly benefit from knowledge of their binding mode to a target. When such information from X-ray crystallography is elusive, computational docking can provide working models. However, few studies have explored docking protocols for macrocycles, since conventional docking methods struggle with the conformational complexity of macrocycles, and also potentially with the shallower topology of their binding sites. Indeed, macrocycle binding mode prediction with the mainstream docking software GOLD has hardly been explored. Here, we present an in-depth study of macrocycle docking with GOLD and the ChemPLP scores. First, we summarize the thorough curation of a test set of 41 protein-macrocycle X-ray structures, raising the issue of lattice contacts with such systems. Rigid docking of the known bioactive conformers was successful (three top ranked poses) for 92.7% of the systems, in absence of crystallographic waters. Thus, without conformational search issues, scoring performed well. However, docking success dropped to 29.3% with the GOLD built-in conformational search. Yet, the success rate doubled to 58.5% when GOLD was supplied with extensive conformer ensembles docked rigidly. The reasons for failure, sampling or scoring, were analyzed, exemplified with particular cases. Overall, binding mode prediction of macrocycles remains challenging, but can be much improved with tailored protocols. The analysis of the interplay between conformational sampling and docking will be relevant to the prospective modelling of macrocycles in general.     

The use of meta-analysis in food contact materials risk assessment

Abstract

As materials intended to be brought into contact with food, food contact materials (FCMs) – including plastics, paper or inks – can transfer their constituents to food under normal or foreseeable use, including direct or indirect food contact. The safety of FCMs in the EU is evaluated by the European Food Safety Authority (EFSA) using risk assessment rules. Results of independent, health-based chemical risk assessments are crucial for the decision-making process to authorize the use of substances in FCMs. However, the risk assessment approach used in the EU has several shortcomings that need to be improved in order to ensure consumer health protection from exposure arising from FCMs. This article presents the use of meta-analysis as a useful tool in chronic risk assessment for substances migrating from FCMs. Meta-analysis can be used for the review and summary of research of FCMs safety in order to provide a more accurate assessment of the impact of exposure with increased statistical power, thus providing more reliable data for risk assessment. The article explains a common methodology of conducting a meta-analysis based on meta-analysis of the dose-effect relationship of cadmium for benchmark dose evaluations performed by EFSA.     

Paratope states in solution improve structure prediction and docking

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Quantitative Exposure-Response Assessment Approaches to Evaluate Acute Inhalation Toxicity of Phosgene

Phosgene has been a long-term subject of toxicological research due to its widespread use, high toxicity, and status as a model of chemically induced lung injury. To take advantage of the abundant data set for the acute inhalation toxicity of phosgene, methods for exposure-response analysis that use more data than the traditional no-observed-adverse-effect level approach were used to perform an exposure-response assessment for phosgene. Categorical regression is particularly useful for acute exposures due to the ability to combine studies of various exposure durations, and thus provide estimates of effect severity for a range of both exposure concentrations and durations. Results from the categorical regression approach were compared to those from parametric curve fitting models (i.e., benchmark concentration models) that make use of information from an entire dose-response, but only for one exposure duration. While categorical regression analysis provided results that were comparable to benchmark concentration results, categorical regression provides an improvement over that technique by accounting for the effects of both exposure concentration and duration on response. The other major advantage afforded by categorical regression is the ability to combine studies, allowing the quantitative use of a larger data set, which increases confidence in the final result.     

A First Exploration of Health Impact Assessment of Chemical Exposure: Assigning Weights to Subclinical Effects Based on Animal Studies

Health impact assessments (HIA) have become an important tool for applying evidence-based policy. Recently, the concept of HIA has been introduced in the field of chemical substances. Two main issues are encountered, i.e., the focus of risk assessment is deriving safe levels and on first signs of adverse effects. These adverse effects, often at a subclinical level, fall outside the scope of a HIA. However, the number of subjects with subclinical effects can be extensive, thus relevant to consider in HIA and subsequent risk management policies and socioeconomic analyses (e.g., under REACH). The approach to include subclinical effects in a HIA relies on the dose–response relationship for toxicological endpoints, which are indicative for subclinical and clinical effects. Assessment of (sub)clinical effect sizes requires expertise from toxicologists, pathologists, and risk assessors. The clinical effect is appraised by a disability weight in the disability adjusted life year (DALY) concept. Subsequently, a derivative thereof, the severity weight, is assigned to parameter value changes in the range of subclinical effect sizes to appraise subclinical effects. Ultimately, if the approach is repeated for many substances, severity weights may be assigned based on changes in endpoints alone, making it a valuable tool for health impact assessors of chemical substances.     

Benchmarking AlphaFold2 on peptide structure prediction

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质量平衡法及其在标准物质定值中的应用进展

为保证不同地区、不同时间测量结果的可比性，测量结果需溯源至适当的、规定的参考标准。对于化学、生物、工程、物理学领域的材料和样品测量，该参考标准为标准物质。由此可见，标准物质的定值对物质的检测及定量是十分重要的。标准物质（reference material，RM）是一种足够均匀的、具有一种或多种相对容易确定的特性值的材料或物质，可用于给材料赋值、评价测量方法及校准测量仪器等。质量平衡法作为标准物质的定量方法之一，是一种常用的纯度测量方法，将水分、灰分、挥发组分、无机元素等杂质的含量从100%中扣除，再根据主要组分在有机组分中的百分比来确定物质纯度。质量平衡法具有较高准确度，能够溯源到国际单位制中的质量单位，且若使用基准方法测量样品中的主成分及各部分杂质以完成整个质量平衡法的测量，质量平衡法则有望成为新的基准方法。基于此，对质量平衡法原理及质量平衡法在标准物质的研制中的应用进行了介绍，并对近期质量平衡法在标准物质中的最新应用进行了总结，以期探索质量平衡法在标准物质研制中的更多可能。     

Performance of density functionals for the structure and energetics of (M–O)0,± (M=Al,Si, Sc–Zn)

We report the results of the performance of 20 exchange–correlation functionals of density functional theory (DFT) in the structure (Metal–Oxygen bond length) and energetical properties (bond dissociation energy, adiabatic ionisation energy, and adiabatic electron affinity) of twelve metal monoxides (M–O, M=Al, Si, Sc–Zn). The calculated results show that the selected DFT functionals have the ability to reproduce the M–O bond length with a mean deviation of 0.01–0.05 Å, the energy values are reproduced with a mean deviation of 0.20–1.00?eV. In general, the functionals with significant HF exchange show decent performance in the calculation of bond length and harmonic vibrational frequency. These functionals show poor performance in energetics. Our calculated results show that the M06-L, B3LYP, and TPSSh functionals give good performance in both structure and energetical properties of metal monoxides. These functionals are recommended for the studies of structure and energetics in metal oxide systems. Further, our studies indicate that M06-L can be used for the studies in larger molecular systems. Among the 20 DFT functionals, the recently developed N12 functional gives poor performance in the studies of metal monoxides. Hence this functional is not recommended for the studies of structure and energetics in metal oxide systems.     

Interfacial water on crystalline silica: a comparative molecular dynamics simulation study

Understanding the properties of interfacial water at solid–liquid interfaces is important in a wide range of applications. Molecular dynamics is becoming a widespread tool for this purpose. Unfortunately, however, the results of such studies are known to strongly depend on the selection of force fields. It is, therefore, of interest to assess the extent by which the implemented force fields can affect the predicted properties of interfacial water. Two silica surfaces, with low and high surface hydroxyl density, respectively, were simulated implementing four force fields. These force fields yield different orientation and flexibility of surface hydrogen atoms, and also different interaction potentials with water molecules. The properties for interfacial water were quantified by calculating contact angles, atomic density profiles, surface density distributions, hydrogen bond density profiles and residence times for water near the solid substrates. We found that at low surface density of hydroxyl groups, the force field strongly affects the predicted contact angle, while at high density of hydroxyl groups, water wets all surfaces considered. From a molecular-level point of view, our results show that the position and intensity of peaks observed from oxygen and hydrogen atomic density profiles are quite different when different force fields are implemented, even when the simulated contact angles are similar. Particularly, the surfaces simulated by the CLAYFF force field appear to attract water more strongly than those simulated by the Bródka and Zerda force field. It was found that the surface density distributions for water strongly depend on the orientation of surface hydrogen atoms. In all cases, we found an elevated number of hydrogen bonds formed between interfacial water molecules. The hydrogen bond density profile does not depend strongly on the force field implemented to simulate the substrate, suggesting that interfacial water assumes the necessary orientation to maximise the number of water–water hydrogen bonds irrespectively of surface properties. Conversely, the residence time for water molecules near the interface strongly depends on the force field and on the flexibility of surface hydroxyl groups. Specifically, water molecules reside for longer times at contact with rigid substrates with high density of hydroxyl groups. These results should be considered when comparisons between simulated and experimental data are attempted.