The accurate prediction of drug-target affinity (DTA) is a crucial step in drug discovery and design. Traditional experiments are very expensive and time-consuming. Recently, deep learning methods have achieved notable performance improvements in DTA prediction. However, one challenge for deep learning-based models is appropriate and accurate representations of drugs and targets, especially the lack of effective exploration of target representations. Another challenge is how to comprehensively capture the interaction information between different instances, which is also important for predicting DTA. In this study, we propose AttentionMGT-DTA, a multi-modal attention-based model for DTA prediction. AttentionMGT-DTA represents drugs and targets by a molecular graph and binding pocket graph, respectively. Two attention mechanisms are adopted to integrate and interact information between different protein modalities and drug-target pairs. The experimental results showed that our proposed model outperformed state-of-the-art baselines on two benchmark datasets. In addition, AttentionMGT-DTA also had high interpretability by modeling the interaction strength between drug atoms and protein residues. Our code is available at https://github.com/JK-Liu7/AttentionMGT-DTA.

Background: Protein-protein interactions (PPIs) are central to a lot of biological processes. Many algorithms and methods have been developed to predict PPIs and protein interaction networks. However, the application of most existing methods is limited since they are difficult to compute and rely on a large number of homologous proteins and interaction marks of protein partners. In this paper, we propose a novel sequence-based approach with multivariate mutual information (MMI) of protein feature representation, for predicting PPIs via Random Forest (RF). Methods: Our method constructs a 638-dimentional vector to represent each pair of proteins. First, we cluster twenty standard amino acids into seven function groups and transform protein sequences into encoding sequences. Then, we use a novel multivariate mutual information feature representation scheme, combined with normalized Moreau-Broto Autocorrelation, to extract features from protein sequence information. Finally, we feed the feature vectors into a Random Forest model to distinguish interaction pairs from non-interaction pairs. Results: To evaluate the performance of our new method, we conduct several comprehensive tests for predicting PPIs. Experiments show that our method achieves better results than other outstanding methods for sequence-based PPIs prediction. Our method is applied to the S.cerevisiae PPIs dataset, and achieves 95.01 % accuracy and 92.67 % sensitivity repectively. For the H.pylori PPIs dataset, our method achieves 87.59 % accuracy and 86.81 % sensitivity respectively. In addition, we test our method on other three important PPIs networks: the one-core network, the multiple-core network, and the crossover network. Conclusions: Compared to the Conjoint Triad method, accuracies of our method are increased by 6.25,2.06 and 18.75 %, respectively. Our proposed method is a useful tool for future proteomics studies.

De novo drug design is crucial in advancing drug discovery, which aims to generate new drugs with specific pharmacological properties. Recently, deep generative models have achieved inspiring progress in generating drug-like compounds. However, the models prioritize a single target drug generation for pharmacological intervention, neglecting the complicated inherent mechanisms of diseases, and influenced by multiple factors. Consequently, developing novel multi-target drugs that simultaneously target specific targets can enhance anti-tumor efficacy and address issues related to resistance mechanisms. To address this issue and inspired by Generative Pre-trained Transformers (GPT) models, we propose an upgraded GPT model with generative adversarial imitation learning for multi-target molecular generation called MTMol-GPT. The multi-target molecular generator employs a dual discriminator model using the Inverse Reinforcement Learning (IRL) method for a concurrently multi-target molecular generation. Extensive results show that MTMol-GPT generates various valid, novel, and effective multi-target molecules for various complex diseases, demonstrating robustness and generalization capability. In addition, molecular docking and pharmacophore mapping experiments demonstrate the drug-likeness properties and effectiveness of generated molecules potentially improve neuropsychiatric interventions. Furthermore, our model’s generalizability is exemplified by a case study focusing on the multi-targeted drug design for breast cancer. As a broadly applicable solution for multiple targets, MTMol-GPT provides new insight into future directions to enhance potential complex disease therapeutics by generating high-quality multi-target molecules in drug discovery. Advancing drug discovery with the vast scale of possible structures of drug-like compounds (between 10²³ and 10⁶⁰) relies on Artificial Intelligence (AI). The process of generating SMILES has been accomplished by using language models like the Generative Pre-trained Transformer (GPT) model. In the meantime, regulating multiple targets to achieve the desired physiological responses is booming for treating complicated diseases. However, the recent deep generative models focus on single-target drug generation, and single-target drugs have limitations, such as requiring higher doses and causing mutations. For example, activation of Src kinase in certain breast cancer cells leads to EGFR phosphorylation and downstream effects. Consequently, designing multi-target molecules against multi-target simultaneously is highly required. Thus, we have proposed an upgraded GPT model MTMol-GPT with generative adversarial imitation learning for generating high-quality multiple targets drug-like compounds. For example, MTMol-GPT generates novel drugs targeting protein pairs such as DRD2 and HTR1A, EGFR and Src. As a broadly applicable tool, MTMol-GPT provides a rapid and accurate method for advancing drug discovery, ensuring the efficient generation of high-quality multi-target drugs.