Novel and versatile artificial intelligence algorithms for investigating possible GHSR1α and DRD1 agonists for Alzheimer's disease.

Hippocampal lesions are recognized as the earliest pathological changes in Alzheimer's disease (AD). Recent researches have shown that the co-activation of growth hormone secretagogue receptor 1α (GHSR1α) and dopamine receptor D1 (DRD1) could recover the function of hippocampal synaptic and cognition. We combined traditional virtual screening technology with artificial intelligence models to screen multi-target agonists for target proteins from TCM database and a novel boost Generalized Regression Neural Network (GRNN) model was proposed in this article to improve the poor adjustability of GRNN. R -square was chosen to evaluate the accuracy of these artificial intelligent models. For the GHSR1α agonist dataset, Adaptive Boosting (AdaBoost), Linear Ridge Regression (LRR), Support Vector Machine (SVM), and boost GRNN achieved good results; the R -square of the test set of these models reached 0.900, 0.813, 0.708, and 0.802, respectively. For the DRD1 agonist dataset, Gradient Boosting (GB), Random Forest (RF), SVM, and boost GRNN achieved good results; the R -square of the test set of these models reached 0.839, 0.781, 0.763, and 0.815, respectively. According to these values of R -square, it is obvious that boost GRNN and SVM have better adaptability for different data sets and boost GRNN is more accurate than SVM. To evaluate the reliability of screening results, molecular dynamics (MD) simulation experiments were performed to make sure that candidates were docked well in the protein binding site. By analyzing the results of these artificial intelligent models and MD experiments, we suggest that 2007_17103 and 2007_13380 are the possible dual-target drugs for Alzheimer's disease (AD).