Virtual screening makes it possible to design and then test up to millions of structures. On the other hand, not every virtual structure can readily be prepared and tested in reality. Therefore, it is necessary to exclude unsuitable candidates, ideally at the beginning of virtual screening campaign. Three main approaches are used to filter out synthetically unfeasible structures: similarity to starting material, retrosynthetic route and complexity of the structure. These techniques vary in computational demands; they can therefore be used in various stages of screening, and/or combined to improve estimation of synthetic feasibility.
- Keywords
- virtuální screening, syntetická dostupnost, komplexita, retrosyntetická analýza, syntetizovatelnost, chemický prostor,
- MeSH
- Databases, Chemical MeSH
- Chemistry, Pharmaceutical MeSH
- Drug Discovery MeSH
- Computer Simulation * MeSH
- Drug Compounding MeSH
- Drug Design MeSH
- Chemistry Techniques, Synthetic MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
Wiley-interscience publication
5th ed. XI, 1064 s. : bar.fot., obr., tab., grafy ; 28 cm
Recent developments in the prediction of local aerosol deposition in human lungs are driven by the fast development of computational simulations. Although such simulations provide results in unbeatable resolution, significant differences among distinct methods of calculation emphasize the need for highly precise experimental data in order to specify boundary conditions and for validation purposes. This paper reviews and critically evaluates available methods for the measurement of single and disperse two-phase flows for the study of respiratory airflow and deposition of inhaled particles, performed both in vivo and in replicas of airways. Limitations and possibilities associated with the experimental methods are discussed and aspects of the computational calculations that can be validated are indicated. The review classifies the methods into following categories: 1) point-wise and planar methods for velocimetry in the airways, 2) classic methods for the measurement of the regional distribution of inhaled particles, 3) standard medical imaging methods applicable to the measurement of the regional aerosol distribution and 4) emerging and nonconventional methods. All methods are described, applications in human airways studies are illustrated, and recommendations for the most useful applications of each method are given.
- MeSH
- Respiratory Tract Absorption MeSH
- Aerosols chemistry MeSH
- Administration, Inhalation MeSH
- Models, Biological MeSH
- Chemistry, Pharmaceutical methods MeSH
- Hydrodynamics MeSH
- Laryngeal Masks * MeSH
- Drug Delivery Systems methods MeSH
- Humans MeSH
- Nebulizers and Vaporizers MeSH
- Permeability MeSH
- Lung drug effects MeSH
- Computer Simulation * MeSH
- Powders chemistry MeSH
- Particle Size MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Regional deposition effects are important in the pulmonary delivery of drugs intended for the topical treatment of respiratory ailments. They also play a critical role in the systemic delivery of drugs with limited lung bioavailability. In recent years, significant improvements in the quality of pulmonary imaging have taken place, however the resolution of current imaging modalities remains inadequate for quantifying regional deposition. Computational Fluid-Particle Dynamics (CFPD) can fill this gap by providing detailed information about regional deposition in the extrathoracic and conducting airways. It is therefore not surprising that the last 15years have seen an exponential growth in the application of CFPD methods in this area. Survey of the recent literature however, reveals a wide variability in the range of modelling approaches used and in the assumptions made about important physical processes taking place during aerosol inhalation. The purpose of this work is to provide a concise critical review of the computational approaches used to date, and to present a benchmark case for validation of future studies in the upper airways. In the spirit of providing the wider community with a reference for quality assurance of CFPD studies, in vitro deposition measurements have been conducted in a human-based model of the upper airways, and several groups within MP1404 SimInhale have computed the same case using a variety of simulation and discretization approaches. Here, we report the results of this collaborative effort and provide a critical discussion of the performance of the various simulation methods. The benchmark case, in vitro deposition data and in silico results will be published online and made available to the wider community. Particle image velocimetry measurements of the flow, as well as additional numerical results from the community, will be appended to the online database as they become available in the future.
- MeSH
- Respiratory Tract Absorption MeSH
- Aerosols chemistry MeSH
- Administration, Inhalation MeSH
- Benchmarking methods MeSH
- Models, Biological MeSH
- Chemistry, Pharmaceutical methods MeSH
- Hydrodynamics MeSH
- Laryngeal Masks * MeSH
- Drug Delivery Systems methods MeSH
- Humans MeSH
- Nebulizers and Vaporizers MeSH
- Permeability MeSH
- Lung drug effects MeSH
- Computer Simulation * MeSH
- Powders chemistry MeSH
- Rheology MeSH
- Particle Size MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
554 s.
- Keywords
- struktury chemické-aktivita biologická,
- Conspectus
- Biochemie. Molekulární biologie. Biofyzika
- NML Fields
- chemie, klinická chemie
- biochemie
The acid dissociation (ionization) constant pK(a) is one of the fundamental properties of organic molecules. We have evaluated different computational strategies and models to predict the pK(a) values of substituted phenols using partial atomic charges. Partial atomic charges for 124 phenol molecules were calculated using 83 approaches containing seven theory levels (MP2, HF, B3LYP, BLYP, BP86, AM1, and PM3), three basis sets (6-31G*, 6-311G, STO-3G), and five population analyses (MPA, NPA, Hirshfeld, MK, and Löwdin). The correlations between pK(a) and various atomic charge descriptors were examined, and the best descriptors were selected for preparing the quantitative structure-property relationship (QSPR) models. One QSPR model was created for each of the 83 approaches to charge calculation, and then the accuracy of all these models was analyzed and compared. The pK(a)s predicted by most of the models correlate strongly with experimental pK(a) values. For example, more than 25% of the models have correlation coefficients (R²) greater than 0.95 and root-mean-square errors smaller than 0.49. All seven examined theory levels are applicable for pK(a) prediction from charges. The best results were obtained for the MP2 and HF level of theory. The most suitable basis set was found to be 6-31G*. The 6-311G basis set provided slightly weaker correlations, and unexpectedly also, the STO-3G basis set is applicable for the QSPR modeling of pK(a). The Mulliken, natural, and Löwdin population analyses provide accurate models for all tested theory levels and basis sets. The results provided by the Hirshfeld population analysis were also acceptable, but the QSPR models based on MK charges show only weak correlations.
- MeSH
- Models, Chemical MeSH
- Chemistry, Pharmaceutical methods statistics & numerical data MeSH
- Phenols analysis chemistry MeSH
- Kinetics MeSH
- Quantitative Structure-Activity Relationship MeSH
- Quantum Theory MeSH
- Pharmaceutical Preparations analysis chemistry MeSH
- Molecular Conformation MeSH
- Computer Simulation MeSH
- Static Electricity MeSH
- Models, Statistical MeSH
- Publication type
- Journal Article MeSH
The Eighth Central European Conference "Chemistry towards Biology" was held in Brno, Czech Republic, on August 28-September 1, 2016 to bring together experts in biology, chemistry and design of bioactive compounds; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topics of the conference covered "Chemistry towards Biology", meaning that the event welcomed chemists working on biology-related problems, biologists using chemical methods, and students and other researchers of the respective areas that fall within the common scope of chemistry and biology. The authors of this manuscript are plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting.
Since its early days in the 19th century, medicinal chemistry has concentrated its efforts on the treatment of diseases, using tools from areas such as chemistry, pharmacology, and molecular biology. The understanding of biological mechanisms and signaling pathways is crucial information for the development of potential agents for the treatment of diseases mainly because they are such complex processes. Given the limitations that the experimental approach presents, computational chemistry is a valuable alternative for the study of these systems and their behavior. Thus, classical molecular dynamics, based on Newton's laws, is considered a technique of great accuracy, when appropriated force fields are used, and provides satisfactory contributions to the scientific community. However, as many configurations are generated in a large MD simulation, methods such as Statistical Inefficiency and Optimal Wavelet Signal Compression Algorithm are great tools that can reduce the number of subsequent QM calculations. Accordingly, this review aims to briefly discuss the importance and relevance of medicinal chemistry allied to computational chemistry as well as to present a case study where, through a molecular dynamics simulation of AMPK protein (50 ns) and explicit solvent (TIP3P model), a minimum number of snapshots necessary to describe the oscillation profile of the protein behavior was proposed. For this purpose, the RMSD calculation, together with the sophisticated OWSCA method was used to propose the minimum number of snapshots.
- MeSH
- Algorithms MeSH
- Chemistry, Pharmaceutical MeSH
- Quantum Theory MeSH
- Humans MeSH
- AMP-Activated Protein Kinases metabolism chemistry MeSH
- Molecular Dynamics Simulation * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
