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Drug discovery and development constitute a laborious and costly undertaking. The success of a drug hinges not only good efficacy but also acceptable absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties. Overall, up to 50% of drug development failures have been contributed from undesirable ADMET profiles. As a multiple parameter objective, the optimization of the ADMET properties is extremely challenging owing to the vast chemical space and limited human expert knowledge. In this study, a freely available platform called Chemical Molecular Optimization, Representation and Translation (ChemMORT) is developed for the optimization of multiple ADMET endpoints without the loss of potency (https://cadd.nscc-tj.cn/deploy/chemmort/). ChemMORT contains three modules: Simplified Molecular Input Line Entry System (SMILES) Encoder, Descriptor Decoder and Molecular Optimizer. The SMILES Encoder can generate the molecular representation with a 512-dimensional vector, and the Descriptor Decoder is able to translate the above representation to the corresponding molecular structure with high accuracy. Based on reversible molecular representation and particle swarm optimization strategy, the Molecular Optimizer can be used to effectively optimize undesirable ADMET properties without the loss of bioactivity, which essentially accomplishes the design of inverse QSAR. The constrained multi-objective optimization of the poly (ADP-ribose) polymerase-1 inhibitor is provided as the case to explore the utility of ChemMORT. [ABSTRACT FROM AUTHOR]

Background Fluorescent detection methods are indispensable tools for chemical biology. However, the frequent appearance of potential fluorescent compound has greatly interfered with the recognition of compounds with genuine activity. Such fluorescence interference is especially difficult to identify as it is reproducible and possesses concentration-dependent characteristic. Therefore, the development of a credible screening tool to detect fluorescent compounds from chemical libraries is urgently needed in early stages of drug discovery. Results In this study, we developed a webserver ChemFLuo for fluorescent compound detection, based on two large and high-quality training datasets containing 4906 blue and 8632 green fluorescent compounds. These molecules were used to construct a group of prediction models based on the combination of three machine learning algorithms and seven types of molecular representations. The best blue fluorescence prediction model achieved with balanced accuracy (BA) = 0.858 and area under the receiver operating characteristic curve (AUC) = 0.931 for the validation set, and BA = 0.823 and AUC = 0.903 for the test set. The best green fluorescence prediction model achieved the prediction accuracy with BA = 0.810 and AUC = 0.887 for the validation set, and BA = 0.771 and AUC = 0.852 for the test set. Besides prediction model, 22 blue and 16 green representative fluorescent substructures were summarized for the screening of potential fluorescent compounds. The comparison with other fluorescence detection tools and theapplication to external validation sets and large molecule libraries have demonstrated the reliability of prediction model for fluorescent compound detection. Conclusion ChemFLuo is a public webserver to filter out compounds with undesirable fluorescent properties, which will benefit the design of high-quality chemical libraries for drug discovery. It is freely available at http://admet.scbdd.com/chemfluo/index/. [ABSTRACT FROM AUTHOR]

Background High-throughput screening (HTS) and virtual screening (VS) have been widely used to identify potential hits from large chemical libraries. However, the frequent occurrence of 'noisy compounds' in the screened libraries, such as compounds with poor drug-likeness, poor selectivity or potential toxicity, has greatly weakened the enrichment capability of HTS and VS campaigns. Therefore, the development of comprehensive and credible tools to detect noisy compounds from chemical libraries is urgently needed in early stages of drug discovery. Results In this study, we developed a freely available integrated python library for negative design, called Scopy, which supports the functions of data preparation, calculation of descriptors, scaffolds and screening filters, and data visualization. The current version of Scopy can calculate 39 basic molecular properties, 3 comprehensive molecular evaluation scores, 2 types of molecular scaffolds, 6 types of substructure descriptors and 2 types of fingerprints. A number of important screening rules are also provided by Scopy, including 15 drug-likeness rules (13 drug-likeness rules and 2 building block rules), 8 frequent hitter rules (four assay interference substructure filters and four promiscuous compound substructure filters), and 11 toxicophore filters (five human-related toxicity substructure filters, three environment-related toxicity substructure filters and three comprehensive toxicity substructure filters). Moreover, this library supports four different visualization functions to help users to gain a better understanding of the screened data, including basic feature radar chart, feature-feature-related scatter diagram, functional group marker gram and cloud gram. Conclusion Scopy provides a comprehensive Python package to filter out compounds with undesirable properties or substructures, which will benefit the design of high-quality chemical libraries for drug design and discovery. It is freely available at https://github.com/kotori-y/Scopy. [ABSTRACT FROM AUTHOR]

In order to form a more rational design of shaft lining, a formula was put forward, in which the porosity of contact surface between shaft lining and surrounding rock np and ratio of radial unloading of surrounding rock η1 was taken into account, based on study of porosity of porous media. The influence of np and η1 on shaft lining was analyzed. The analysis shows that the influence becomes strong with increase of np and the impact of surrounding rock pressure becomes weak with increase of np. Raising η1 rationally under precondition of avoiding stripping of solid skeleton should be done in design and construction. The result of the new method is smaller than that of current method and smaller than the pore water pressure obviously. [ABSTRACT FROM AUTHOR]

In order to thoroughly investigate the load of outer shaft lining in deep aqueous bed rock area, in-situ measurements on freezing pressure of outer shaft lining were carried out in bed rock in Hujierte coalfield in Chinese Erdos. The in-situ measurement results reveal that the process of freezing pressure can be described by 4 periods: dramatic increase period, slow increase period, rapid increase period and gradual decrease period. The freezing pressure is mainly affected by rock moisture content and rock strength, but the rocks buried deep H affects little. The freezing pressure reaches 76.4% ~ 89. 8% of the maximum freezing pressure Pmax at 10 ~ 15 days after concrete pouring. Therefore, it is recommended using 7 days concrete strength index to guarantee the safety of outer shaft lining during the early period. The freezing pressure reaches the maximum value Pmax at 80 ~100 days after concrete pouring, the measured value of Pmax is 1.08 ~ 1.74 MPa. Pmax is much smaller than hydrostatic pressure P0 and the maximum freezing pressure Pω in deep alluvium. [ABSTRACT FROM AUTHOR]

Lipophilicity, as evaluated by the n -octanol/buffer solution distribution coefficient at pH = 7.4 (log  D 7.4 ), is a major determinant of various absorption, distribution, metabolism, elimination, and toxicology (ADMET) parameters of drug candidates. In this study, we developed several quantitative structure-property relationship (QSPR) models to predict log  D 7.4 based on a large and structurally diverse data set. Eight popular machine learning algorithms were employed to build the prediction models with 43 molecular descriptors selected by a wrapper feature selection method. The results demonstrated that XGBoost yielded better prediction performance than any other single model ( R T 2 = 0.906 and RMSE T = 0.395). Moreover, the consensus model from the top three models could continue to improve the prediction performance ( R T 2 = 0.922 and RMSE T = 0.359). The robustness, reliability, and generalization ability of the models were strictly evaluated by the Y-randomization test and applicability domain analysis. Moreover, the group contribution model based on 110 atom types and the local models for different ionization states were also established and compared to the global models. The results demonstrated that the descriptor-based consensus model is superior to the group contribution method, and the local models have no advantage over the global models. Finally, matched molecular pair (MMP) analysis and descriptor importance analysis were performed to extract transformation rules and give some explanations related to log  D 7.4 . In conclusion, we believe that the consensus model developed in this study can be used as a reliable and promising tool to evaluate log  D 7.4 in drug discovery.

Based on a grid (25 m X 25 m) equidistant sampling, the spatial variability of pH, organic matter, total nitrogen, available phosphorus, CEC and three typical heavy metal elements Cd, As and Pb in soil tillage layer (0-20 cm) were analyzed by using GIS and Geostatistics in the paddy field of 3.56 hm 2 in Beishan Town, Changsha County, Hunan Province. The results showed that soil pH value and Pb content showed weak variation, and other indexes showed moderate variation. The order of variation was following available phosphorus ＞ Cd ＞ total nitrogen ＞ organic matter ＞ CEC ＞ As ＞ Pb ＞ pH. Results of the semi-variance test showed that the best fitting model of the semi-variance function of organic matter, available phosphorus and As was exponential, and the best semi-variance function of pH, total nitrogen, CEC, Cd, Pb was spherical. All the indicators had a strong spatial correlation except for CEC, which showed moderate spatial correlation. Kriging interpolation analysis showed that pH, total nitrogen, CEC, Pb were plaque distribution, while organic matter, available phosphorus, Cd and As were block and banded distribution. Vegetation, topography and human activities were the main factors driving the variation of soil nutrients and heavy metals in the study area. The correlation between soil nutrients and heavy metals content was significant, among which pH and organic matter, Cd and Pb reached a very significant correlation level.