Cell-penetrating peptides (CPPs) have great potential to deliver bioactive agents into cells. Although there have been many recent advances in CPP-related research, it is still important to develop more efficient CPPs. The development of CPPs by in silico methods is a very useful addition to experimental methods, but in many cases it can lead to a large number of false-positive results. In this study, we developed a deep-learning-based CPP prediction method, AiCPP, to develop novel CPPs. AiCPP uses a large number of peptide sequences derived from human-reference proteins as a negative set to reduce false-positive predictions and adopts a method to learn small-length peptide sequence motifs that may have CPP tendencies. Using AiCPP, we found that short peptide sequences derived from amyloid precursor proteins are efficient new CPPs, and experimentally confirmed that these CPP sequences can be further optimized.

G protein-coupled receptors (GPCRs) play vital roles in various physiological processes, making them attractive drug discovery targets. Meanwhile, deep learning techniques have revolutionized drug discovery by facilitating efficient tools for expediting the identification and optimization of ligands. However, existing models for the GPCRs often focus on single-target or a small subset of GPCRs or employ binary classification, constraining their applicability for high throughput virtual screening. To address these issues, we introduce AiGPro, a novel multitask model designed to predict small molecule agonists (EC50) and antagonists (IC50) across the 231 human GPCRs, making it a first-in-class solution for large-scale GPCR profiling. Leveraging multi-scale context aggregation and bidirectional multi-head cross-attention mechanisms, our approach demonstrates that ensemble models may not be necessary for predicting complex GPCR states and small molecule interactions. Through extensive validation using stratified tenfold cross-validation, AiGPro achieves robust performance with Pearson's correlation coefficient of 0.91, indicating broad generalizability. This breakthrough sets a new standard in the GPCR studies, outperforming previous studies. Moreover, our first-in-class multi-tasking model can predict agonist and antagonist activities across a wide range of GPCRs, offering a comprehensive perspective on ligand bioactivity within this diverse superfamily. To facilitate easy accessibility, we have deployed a web-based platform for model access at https://aicadd.ssu.ac.kr/AiGPro . Scientific Contribution We introduce a deep learning-based multi-task model to generalize the agonist and antagonist bioactivity prediction for GPCRs accurately. The model is implemented on a user-friendly web server to facilitate rapid screening of small-molecule libraries, expediting GPCR-targeted drug discovery. Covering a diverse set of 231 GPCR targets, the platform delivers a robust, scalable solution for advancing GPCR-focused therapeutic development. The proposed framework incorporates an innovative dual-label prediction strategy, enabling the simultaneous classification of molecules as agonists, antagonists, or both. Each prediction is further accompanied by a confidence score, offering a quantitative measure of activity likelihood. This advancement moves beyond conventional models focusing solely on binding affinity, providing a more comprehensive understanding of ligand-receptor interactions. At the core of our model lies the Bi-Directional Multi-Head Cross-Attention (BMCA) module, a novel architecture that captures forward and backward contextual embeddings of protein and ligand features. By leveraging BMCA, the model effectively integrates structural and sequence-level information, ensuring a precise representation of molecular interactions. Results show that this approach is highly accurate in binding affinity predictions and consistent across diverse GPCR families. By unifying agonist and antagonist bioactivity prediction into a single model architecture, we bridge a critical gap in GPCR modeling. This enhances prediction accuracy and accelerates virtual screening workflows, offering a valuable and innovative solution for advancing GPCR-targeted drug discovery.

The discovery of selective and potent kinase inhibitors is crucial for the treatment of various diseases, but the process is challenging due to the high structural similarity among kinases. Efficient kinome-wide bioactivity profiling is essential for understanding kinase function and identifying selective inhibitors. In this study, we propose AiKPro, a deep learning model that combines structure-validated multiple sequence alignments and molecular 3D conformer ensemble descriptors to predict kinase-ligand binding affinities. Our deep learning model uses an attention-based mechanism to capture complex patterns in the interactions between the kinase and the ligand. To assess the performance of AiKPro, we evaluated the impact of descriptors, the predictability for untrained kinases and compounds, and kinase activity profiling based on odd ratios. Our model, AiKPro, shows good Pearson’s correlation coefficients of 0.88 and 0.87 for the test set and for the untrained sets of compounds, respectively, which also shows the robustness of the model. AiKPro shows good kinase-activity profiles across the kinome, potentially facilitating the discovery of novel interactions and selective inhibitors. Our approach holds potential implications for the discovery of novel, selective kinase inhibitors and guiding rational drug design.

The discovery of selective and potent kinase inhibitors is crucial for the treatment of various diseases, but the process is challenging due to the high structural similarity among kinases. Efficient kinome-wide bioactivity profiling is essential for understanding kinase function and identifying selective inhibitors. In this study, we propose AiKPro, a deep learning model that combines structure-validated multiple sequence alignments (svMSA) and molecular 3D conformer ensemble descriptors (3CED) to predict kinase-ligand binding affinities. Our deep learning model uses an attention-based mechanism to capture complex patterns in the interactions between the kinase and the ligand. To assess the performance of AiKPro, we evaluated the impact of descriptors, the predictability for untrained kinases and compounds, and kinase activity profiling based on odd ratios. Our model, AiKPro, shows good Pearson's correlation coefficients of 0.88 and 0.87 for the test set and for the untrained sets of compounds, respectively, which also shows the robustness of the model. AiKPro shows good kinase-activity profiles across the kinome, potentially facilitating the discovery of novel interactions and selective inhibitors. Our approach holds potential implications for the discovery of novel, selective kinase inhibitors and guiding rational drug design.