Revisiting Structure-activity Relationships: Unleashing the potential of selective Janus kinase 1 inhibitors.

Janus kinases (JAKs), a kind of non-receptor tyrosine kinases, the function has been implicated in the regulation of cell proliferation, differentiation and apoptosis, immune, inflammatory response and malignancies. Among them, JAK1 represents an essential target for modulating cytokines involved in inflammation and immune function. Rheumatoid arthritis, atopic dermatitis, ulcerative colitis and psoriatic arthritis are areas where approved JAK1 drugs have been applied for the treatment. In the review, we provided a brief introduction to JAK1 inhibitors in market and clinical trials. The structures of high active JAK1 compounds (IC50 ≤ 0.1 nM) were highlighted, with primary focus on structure-activity relationship and selectivity. Moreover, the druggability processes of approved drugs and high active compounds were analyzed. In addition, the issues involved in JAK1 compounds clinical application as well as strategies to surmount these challenges, were discussed.

Reliable prediction of cannabinoid receptor 2 ligand by machine learning based on combined fingerprints.

Cannabinoid receptors, as part of the family of the G protein-coupled receptors (GPCRs), are involved in various physiological functions. Its subtype cannabinoid receptor subtype 2 (CB2), mainly distributed in the periphery, is a crucial therapeutic target for anti-epileptic, anti-inflammation, anti-fibrosis, and bone metabolism regulation, and it regulates these physiological functions without psychiatric side effects. Recently machine learning methods for predicting biophysics properties have attracted much attention. Successful application of machine learning usually highly depends on the appropriate representation of the compounds. In this study, we comprehensively evaluate the performance of the descriptor-based models (including XGBoost, Random Forest, and KNN) and two graph-based models (D-MPNN, MolMap) for the prediction of the CB2 regulators, and found that XGBoost offers outstanding performance for both regression tasks and classification tasks. 13 different molecular fingerprints and 12 descriptors, as well as their combination were further screened; AvalonFP + AtomPairFP + RDkitFP + MorganFP and AtomPairFP + MorganFP + AvalonFP were the optimum combinations for regression task (R2 increase to 0.667) and classification task (AUC-ROC increase to 0.933), respectively. Specifically, the best XGBoost regression model with optimum features achieves better performance than Mizera's QSAR model on the same dataset developed by Mizera (R2 0.664 versus 0.62). It also achieves optimal performance with an AUC-ROC of 0.917 on the external validation set. By comparison, MolMap and D-MPNN only provide 0.912 and 0.898. The Shapley additive explanation method was used to interpret the models, and features importance were shown for both regression and classification task. The XGBoost model equipped with essential molecular fingerprints combination in this paper may provide valuable clues to designing novel CB2 ligands and developing models for other properties prediction.

Predicting hERG channel blockers with directed message passing neural networks.

Compounds with human ether-à-go-go related gene (hERG) blockade activity may cause severe cardiotoxicity. Assessing the hERG liability in the early stages of the drug discovery process is important, and the in silico methods for predicting hERG channel blockers are actively pursued. In the present study, the directed message passing neural network (D-MPNN) was applied to construct classification models for identifying hERG blockers based on diverse datasets. Several descriptors and fingerprints were tested along with the D-MPNN model. Among all these combinations, D-MPNN with the moe206 descriptors generated from MOE (D-MPNN + moe206) showed significantly improved performances. The AUC-ROC values of the D-MPNN + moe206 model reached 0.956 ± 0.005 under random split and 0.922 ± 0.015 under scaffold split on Cai's hERG dataset, respectively. Moreover, the comparisons between our models and several recently reported machine learning models were made based on various datasets. Our results indicated that the D-MPNN + moe206 model is among the best classification models. Overall, the excellent performance of the DMPNN + moe206 model achieved in this study highlights its potential application in the discovery of novel and effective hERG blockers.