Revolutionizing GPCR-ligand predictions: DeepGPCR with experimental validation for high-precision drug discovery.

G-protein coupled receptors (GPCRs), crucial in various diseases, are targeted of over 40% of approved drugs. However, the reliable acquisition of experimental GPCRs structures is hindered by their lipid-embedded conformations. Traditional protein-ligand interaction models falter in GPCR-drug interactions, caused by limited and low-quality structures. Generalized models, trained on soluble protein-ligand pairs, are also inadequate. To address these issues, we developed two models, DeepGPCR_BC for binary classification and DeepGPCR_RG for affinity prediction. These models use non-structural GPCR-ligand interaction data, leveraging graph convolutional networks and mol2vec techniques to represent binding pockets and ligands as graphs. This approach significantly speeds up predictions while preserving critical physical-chemical and spatial information. In independent tests, DeepGPCR_BC surpassed Autodock Vina and Schrödinger Dock with an area under the curve of 0.72, accuracy of 0.68 and true positive rate of 0.73, whereas DeepGPCR_RG demonstrated a Pearson correlation of 0.39 and root mean squared error of 1.34. We applied these models to screen drug candidates for GPR35 (Q9HC97), yielding promising results with three (F545-1970, K297-0698, S948-0241) out of eight candidates. Furthermore, we also successfully obtained six active inhibitors for GLP-1R. Our GPCR-specific models pave the way for efficient and accurate large-scale virtual screening, potentially revolutionizing drug discovery in the GPCR field.

Crystal growth engineering and origin of the weak ferromagnetism in antiferromagnetic matrix of orthochromates from t-e orbital hybridization.

We report a combined experimental and theoretical study on intriguing magnetic properties of quasiferroelectric orthochromates. Large single crystals of the family of RECrO3 (RE = Y, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu) compounds were successfully grown. Neutron Laue study indicates a good quality of the obtained single crystals. Applied magnetic field and temperature dependent magnetization measurements reveal their intrinsic magnetic properties, especially the antiferromagnetic (AFM) transition temperatures. Density functional theory studies of the electronic structures were carried out using the Perdew-Burke-Ernzerhof functional plus Hubbard U method. Crystallographic information and magnetism were theoretically optimized systematically. When RE3+ cations vary from Y3+ and Eu3+ to Lu3+ ions, the calculated t-e orbital hybridization degree and Néel temperature behave similarly to the experimentally determined AFM transition temperature with variation in cationic radius. We found that the t-e hybridization is anisotropic, causing a magnetic anisotropy of Cr3+ sublattices. This was evaluated with the nearest-neighbor J 1-J 2 model. Our research provides a picture of the electronic structures during the t-e hybridization process while changing RE ions and sheds light on the nature of the weak ferromagnetism coexisting with predominated antiferromagnetism. The available large RECrO3 single crystals build a platform for further studies of orthochromates.