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Predicting the sensory properties of compounds is challenging due to the subjective nature of the experimental measurements. This testing relies on a panel of human participants and is therefore also expensive and time-consuming. We describe the application of a state-of-the-art deep learning method, Alchemite™, to the imputation of sparse physicochemical and sensory data and compare the results with conventional quantitative structure-activity relationship methods and a multi-target graph convolutional neural network. The imputation model achieved a substantially higher accuracy of prediction, with improvements in R 2 between 0.26 and 0.45 over the next best method for each sensory property. We also demonstrate that robust uncertainty estimates generated by the imputation model enable the most accurate predictions to be identified and that imputation also more accurately predicts activity cliffs, where small changes in compound structure result in large changes in sensory properties. In combination, these results demonstrate that the use of imputation, based on data from less expensive, early experiments, enables better selection of compounds for more costly studies, saving experimental time and resources., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Acetylcholinesterase (AChE) is both a therapeutic target for Alzheimer's disease and a target for organophosphorus, carbamates and chemical warfare agents. Prediction of the likelihood of compounds interacting with this enzyme is therefore important from both therapeutic and toxicological perspectives., Materials and Methods: Support vector machine classification and regression models with molecular descriptors derived from Shape Signatures and the Molecular Operating Environment (MOE) application software were built and tested using a set of piperidine AChE inhibitors (N = 110)., Results: The combination of the alignment free Shape Signatures and 2D MOE descriptors with the Support Vector Regression method outperforms the models based solely on 2D and internal 3D (i3D) MOE descriptors, and is comparable with the best previously reported PLS model based on CoMFA molecular descriptors (r(2)(test,SVR) = 0.48 vs. r(2)(test,PLS) = 0.47 from Sutherland et al. J Med Chem 47:5541-5554, 2004). Support Vector Classification algorithms proved superior to a classifier based on scores from the molecular docking program GOLD, with the overall prediction accuracies being Q(SVC(10CV)) = 74% and Q(SVC(LNO)) = 67% vs. Q(GOLD) = 56%., Conclusions: These new machine learning models with combined descriptor schemes may find utility for predicting novel AChE inhibitors.

Purpose: The human pregnane X receptor (PXR) is a transcriptional regulator of many genes involved in xenobiotic metabolism and excretion. Reliable prediction of high affinity binders with this receptor would be valuable for pharmaceutical drug discovery to predict potential toxicological responses, Materials and Methods: Computational models were developed and validated for a dataset consisting of human PXR (PXR) activators and non-activators. We used support vector machine (SVM) algorithms with molecular descriptors derived from two sources, Shape Signatures and the Molecular Operating Environment (MOE) application software. We also employed the molecular docking program GOLD in which the GoldScore method was supplemented with other scoring functions to improve docking results., Results: The overall test set prediction accuracy for PXR activators with SVM was 72% to 81%. This indicates that molecular shape descriptors are useful in classification of compounds binding to this receptor. The best docking prediction accuracy (61%) was obtained using 1D Shape Signature descriptors as a weighting factor to the GoldScore. By pooling the available human PXR data sets we revealed those molecular features that are associated with human PXR activators., Conclusions: These combined computational approaches using molecular shape information may assist scientists to more confidently identify PXR activators.

Purpose: The goals of the present study were to apply a generalized regression model and support vector machine (SVM) models with Shape Signatures descriptors, to the domain of blood-brain barrier (BBB) modeling., Materials and Methods: The Shape Signatures method is a novel computational tool that was used to generate molecular descriptors utilized with the SVM classification technique with various BBB datasets. For comparison purposes we have created a generalized linear regression model with eight MOE descriptors and these same descriptors were also used to create SVM models., Results: The generalized regression model was tested on 100 molecules not in the model and resulted in a correlation r2 = 0.65. SVM models with MOE descriptors were superior to regression models, while Shape Signatures SVM models were comparable or better than those with MOE descriptors. The best 2D shape signature models had 10-fold cross validation prediction accuracy between 80-83% and leave-20%-out testing prediction accuracy between 80-82% as well as correctly predicting 84% of BBB+ compounds (n = 95) in an external database of drugs., Conclusions: Our data indicate that Shape Signatures descriptors can be used with SVM and these models may have utility for predicting blood-brain barrier permeation in drug discovery.

The OPLS-AA all-atom force field and the Analytical Generalized Born plus Non-Polar (AGBNP) implicit solvent model, in conjunction with torsion angle conformational search protocols based on the Protein Local Optimization Program (PLOP), are shown to be effective in predicting the native conformations of 57 9-residue and 35 13-residue loops of a diverse series of proteins with low sequence identity. The novel nonpolar solvation free energy estimator implemented in AGBNP augmented by correction terms aimed at reducing the occurrence of ion pairing are important to achieve the best prediction accuracy. Extended versions of the previously developed PLOP-based conformational search schemes based on calculations in the crystal environment are reported that are suitable for application to loop homology modeling without the crystal environment. Our results suggest that in general the loop backbone conformation is not strongly influenced by crystal packing. The application of the temperature Replica Exchange Molecular Dynamics (T-REMD) sampling method for a few examples where PLOP sampling is insufficient are also reported. The results reported indicate that the OPLS-AA/AGBNP effective potential is suitable for high-resolution modeling of proteins in the final stages of homology modeling and/or protein crystallographic refinement.

We analyze the melting of a quasi-two-dimensional metallic system using the results of a series of Monte Carlo simulations of an array of Pb atoms. The system was chosen to model the melting behavior observed for the monolayer of Pb that segregates in the liquid-vapor interface of a dilute Pb in Ga alloy [B. Yang et al., Proc. Natl. Acad. Sci. USA 96, 13 009 (1999)]. Our calculations employed a realistic pair interaction potential between lead pseudoatoms, one that is known to describe accurately the properties of the three-dimensional metal near the melting point. Our results reveal that in the quasi-two-dimensional Pb system melting is a two-stage process which proceeds through formation of a stable intermediate hexatic phase, in agreement with the prediction of the Kosterlitz-Thouless-Halperin-Nelson-Young theory. Both the solid-to-hexatic and the hexatic-to-liquid transitions are found to be first order in our simulations.