Absorption, distribution, metabolism, and excretion (ADME) studies are critical for drug discovery. Conventionally, these tasks, together with other chemical property predictions, rely on domain-specific feature descriptors, or fingerprints. Following the recent success of neural networks, we developed Chemi-Net, a completely data-driven, domain knowledge-free, deep learning method for ADME property prediction. To compare the relative performance of Chemi-Net with Cubist, one of the popular machine learning programs used by Amgen, a large-scale ADME property prediction study was performed on-site at Amgen. For all 13 data sets, Chemi-Net resulted in higher R2 values compared with the Cubist benchmark. The median R2 increase rate over Cubist was 26.7%. We expect that the significantly increased accuracy of ADME prediction seen with Chemi-Net over Cubist will greatly accelerate drug discovery.
Thermostability issue of protein point mutations is a common occurrence in protein engineering. An application which predicts the thermostability of mutants can be helpful for guiding decision making process in protein design via mutagenesis. An in silico point mutation scanning method is frequently used to find “hot spots” in proteins for focused mutagenesis. ProTherm (http://gibk26.bio.kyutech.ac.jp/jouhou/Protherm/protherm.html) is a public database that consists of thousands of protein mutants’ experimentally measured thermostability. Two data sets based on two differently measured thermostability properties of protein single point mutations, namely the unfolding free energy change (ddG) and melting temperature change (dTm) were obtained from this database. Folding free energy change calculation from Rosetta, structural information of the point mutations as well as amino acid physical properties were obtained for building thermostability prediction models with informatics modeling tools. Five supervised machine learning methods (support vector machine, random forests, artificial neural network, naïve Bayes classifier, K nearest neighbor) and partial least squares regression are used for building the prediction models. Binary and ternary classifications as well as regression models were built and evaluated. Data set redundancy and balancing, the reverse mutations technique, feature selection, and comparison to other published methods were discussed. Rosetta calculated folding free energy change ranked as the most influential features in all prediction models. Other descriptors also made significant contributions to increasing the accuracy of the prediction models.
Chemical stability is a major concern in the development of protein therapeutics due to its impact on both efficacy and safety. Protein “hotspots” are amino acid residues that are subject to various chemical modifications, including deamidation, isomerization, glycosylation, oxidation etc. A more accurate prediction method for potential hotspot residues would allow their elimination or reduction as early as possible in the drug discovery process. In this work, we focus on prediction models for asparagine (Asn) deamidation. Sequence-based prediction method simply identifies the NG motif (amino acid asparagine followed by a glycine) to be liable to deamidation. It still dominates deamidation evaluation process in most pharmaceutical setup due to its convenience. However, the simple sequence-based method is less accurate and often causes over-engineering a protein. We introduce structure-based prediction models by mining available experimental and structural data of deamidated proteins. Our training set contains 194 Asn residues from 25 proteins that all have available high-resolution crystal structures. Experimentally measured deamidation half-life of Asn in penta-peptides as well as 3D structure-based properties, such as solvent exposure, crystallographic B-factors, local secondary structure and dihedral angles etc., were used to train prediction models with several machine learning algorithms. The prediction tools were cross-validated as well as tested with an external test data set. The random forest model had high enrichment in ranking deamidated residues higher than non-deamidated residues while effectively eliminated false positive predictions. It is possible that such quantitative protein structure–function relationship tools can also be applied to other protein hotspot predictions. In addition, we extensively discussed metrics being used to evaluate the performance of predicting unbalanced data sets such as the deamidation case.
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