FSM-DDTR: End-to-end feedback strategy for multi-objective De Novo drug design using transformers.

The design of compounds that target specific biological functions with relevant selectivity is critical in the context of drug discovery, especially due to the polypharmacological nature of most existing drug molecules. In recent years, in silico-based methods combined with deep learning have shown promising results in the de novo drug design challenge, leading to potential leads for biologically interesting targets. However, several of these methods overlook the importance of certain properties, such as validity rate and target selectivity, or simplify the generative process by neglecting the multi-objective nature of the pharmacological space. In this study, we propose a multi-objective Transformer-based architecture to generate drug candidates with desired molecular properties and increased selectivity toward a specific biological target. The framework consists of a Transformer-Decoder Generator that generates novel and valid compounds in the SMILES format notation, a Transformer-Encoder Predictor that estimates the binding affinity toward the biological target, and a feedback loop combined with a multi-objective optimization strategy to rank the generated molecules and condition the generating distribution around the targeted properties. The results demonstrate that the proposed architecture can generate novel and synthesizable small compounds with desired pharmacological properties toward a biologically relevant target. The unbiased Transformer-based Generator achieved superior performance in the novelty rate (97.38%) and comparable performance in terms of internal diversity, uniqueness, and validity against state-of-the-art baselines. The optimization of the unbiased Transformer-based Generator resulted in the generation of molecules exhibiting high binding affinity toward the Adenosine A2A Receptor (AA2AR) and possessing desirable physicochemical properties, where 99.36% of the generated molecules follow Lipinski's rule of five. Furthermore, the implementation of a feedback strategy, in conjunction with a multi-objective algorithm, effectively shifted the distribution of the generated molecules toward optimal values of molecular weight, molecular lipophilicity, topological polar surface area, synthetic accessibility score, and quantitative estimate of drug-likeness, without the necessity of prior training sets comprising molecules endowed with pharmacological properties of interest. Overall, this research study validates the applicability of a Transformer-based architecture in the context of drug design, capable of exploring the vast chemical representation space to generate novel molecules with improved pharmacological properties and target selectivity. The data and source code used in this study are available at: https://github.com/larngroup/FSM-DDTR.

DTITR: End-to-end drug-target binding affinity prediction with transformers.

The accurate identification of Drug-Target Interactions (DTIs) remains a critical turning point in drug discovery and understanding of the binding process. Despite recent advances in computational solutions to overcome the challenges of in vitro and in vivo experiments, most of the proposed in silico-based methods still focus on binary classification, overlooking the importance of characterizing DTIs with unbiased binding strength values to properly distinguish primary interactions from those with off-targets. Moreover, several of these methods usually simplify the entire interaction mechanism, neglecting the joint contribution of the individual units of each binding component and the interacting substructures involved, and have yet to focus on more explainable and interpretable architectures. In this study, we propose an end-to-end Transformer-based architecture for predicting drug-target binding affinity (DTA) using 1D raw sequential and structural data to represent the proteins and compounds. This architecture exploits self-attention layers to capture the biological and chemical context of the proteins and compounds, respectively, and cross-attention layers to exchange information and capture the pharmacological context of the DTIs. The results show that the proposed architecture is effective in predicting DTA, achieving superior performance in both correctly predicting the value of interaction strength and being able to correctly discriminate the rank order of binding strength compared to state-of-the-art baselines. The combination of multiple Transformer-Encoders was found to result in robust and discriminative aggregate representations of the proteins and compounds for binding affinity prediction, in which the addition of a Cross-Attention Transformer-Encoder was identified as an important block for improving the discriminative power of these representations. Overall, this research study validates the applicability of an end-to-end Transformer-based architecture in the context of drug discovery, capable of self-providing different levels of potential DTI and prediction understanding due to the nature of the attention blocks. The data and source code used in this study are available at: https://github.com/larngroup/DTITR.

Designing optimized drug candidates with Generative Adversarial Network.

Drug design is an important area of study for pharmaceutical businesses. However, low efficacy, off-target delivery, time consumption, and high cost are challenges and can create barriers that impact this process. Deep Learning models are emerging as a promising solution to perform de novo drug design, i.e., to generate drug-like molecules tailored to specific needs. However, stereochemistry was not explicitly considered in the generated molecules, which is inevitable in targeted-oriented molecules. This paper proposes a framework based on Feedback Generative Adversarial Network (GAN) that includes optimization strategy by incorporating Encoder-Decoder, GAN, and Predictor deep models interconnected with a feedback loop. The Encoder-Decoder converts the string notations of molecules into latent space vectors, effectively creating a new type of molecular representation. At the same time, the GAN can learn and replicate the training data distribution and, therefore, generate new compounds. The feedback loop is designed to incorporate and evaluate the generated molecules according to the multiobjective desired property at every epoch of training to ensure a steady shift of the generated distribution towards the space of the targeted properties. Moreover, to develop a more precise set of molecules, we also incorporate a multiobjective optimization selection technique based on a non-dominated sorting genetic algorithm. The results demonstrate that the proposed framework can generate realistic, novel molecules that span the chemical space. The proposed Encoder-Decoder model correctly reconstructs 99% of the datasets, including stereochemical information. The model's ability to find uncharted regions of the chemical space was successfully shown by optimizing the unbiased GAN to generate molecules with a high binding affinity to the Kappa Opioid and Adenosine [Formula: see text] receptor. Furthermore, the generated compounds exhibit high internal and external diversity levels 0.88 and 0.94, respectively, and uniqueness.

Explainable deep drug-target representations for binding affinity prediction.

BACKGROUND: Several computational advances have been achieved in the drug discovery field, promoting the identification of novel drug-target interactions and new leads. However, most of these methodologies have been overlooking the importance of providing explanations to the decision-making process of deep learning architectures. In this research study, we explore the reliability of convolutional neural networks (CNNs) at identifying relevant regions for binding, specifically binding sites and motifs, and the significance of the deep representations extracted by providing explanations to the model's decisions based on the identification of the input regions that contributed the most to the prediction. We make use of an end-to-end deep learning architecture to predict binding affinity, where CNNs are exploited in their capacity to automatically identify and extract discriminating deep representations from 1D sequential and structural data. RESULTS: The results demonstrate the effectiveness of the deep representations extracted from CNNs in the prediction of drug-target interactions. CNNs were found to identify and extract features from regions relevant for the interaction, where the weight associated with these spots was in the range of those with the highest positive influence given by the CNNs in the prediction. The end-to-end deep learning model achieved the highest performance both in the prediction of the binding affinity and on the ability to correctly distinguish the interaction strength rank order when compared to baseline approaches. CONCLUSIONS: This research study validates the potential applicability of an end-to-end deep learning architecture in the context of drug discovery beyond the confined space of proteins and ligands with determined 3D structure. Furthermore, it shows the reliability of the deep representations extracted from the CNNs by providing explainability to the decision-making process.

Drug-Target Interaction Prediction: End-to-End Deep Learning Approach.

The discovery of potential Drug-Target Interactions (DTIs) is a determining step in the drug discovery and repositioning process, as the effectiveness of the currently available antibiotic treatment is declining. Although putting efforts on the traditional in vivo or in vitro methods, pharmaceutical financial investment has been reduced over the years. Therefore, establishing effective computational methods is decisive to find new leads in a reasonable amount of time. Successful approaches have been presented to solve this problem but seldom protein sequences and structured data are used together. In this paper, we present a deep learning architecture model, which exploits the particular ability of Convolutional Neural Networks (CNNs) to obtain 1D representations from protein sequences (amino acid sequence) and compounds SMILES (Simplified Molecular Input Line Entry System) strings. These representations can be interpreted as features that express local dependencies or patterns that can then be used in a Fully Connected Neural Network (FCNN), acting as a binary classifier. The results achieved demonstrate that using CNNs to obtain representations of the data, instead of the traditional descriptors, lead to improved performance. The proposed end-to-end deep learning method outperformed traditional machine learning approaches in the correct classification of both positive and negative interactions.