Drug Design and Disease Diagnosis: The Potential of Deep Learning Models in Biology

Early prediction and detection enable reduced transmission of human diseases and provide healthcare professionals ample time to make subsequent diagnoses and treatment strategies. This, in turn, aids in saving more lives and results in lower medical costs. Designing small chemical molecules to treat fatal disorders is also urgently needed to address the high death rate of these diseases worldwide. A recent analysis of published literature suggested that deep learning (DL) based models apply more potential algorithms to hybrid databases of chemical data. Considering the above, we first discussed the concept of DL architectures and their applications in drug development and diagnostics in this review. Although DL-based approaches have applications in several fields, in the following sections of the arti-cle, we focus on recent developments of DL-based techniques in biology, notably in structure predic-tion, cancer drug development, COVID infection diagnostics, and drug repurposing strategies. Each review section summarizes several cutting-edge, recently developed DL-based techniques. Additionally, we introduced the approaches presented in our group, whose prediction accuracy is relatively compara-ble with current computational models. We concluded the review by discussing the benefits and draw-backs of DL techniques and outlining the future paths for data collecting and developing efficient computational models.Copyright © 2023 Bentham Science Publishers.

Drug–Target Interaction Deep Learning-Based Model Identifies the Flavonoid Troxerutin as a Candidate TRPV1 Antagonist

Based on the advances made by artificial intelligence (AI) technologies in drug discovery, including target identification, hit molecule identification, and lead optimization, this study investigated natural compounds that could act as transient receptor potential vanilloid 1 (TRPV1) channel protein antagonists. Using a molecular transformer drug–target interaction (MT-DTI) model, troxerutin was predicted to be a TRPV1 antagonist at IC50 582.73 nM. In a TRPV1-overexpressing HEK293T cell line, we found that troxerutin antagonized the calcium influx induced by the TRPV1 agonist capsaicin in vitro. A structural modeling and docking experiment of troxerutin and human TRPV1 confirmed that troxerutin could be a TRPV1 antagonist. A small-scale clinical trial consisting of 29 participants was performed to examine the efficacy of troxerutin in humans. Compared to a vehicle lotion, both 1% and 10% w/v troxerutin lotions reduced skin irritation, as measured by skin redness induced by capsaicin, suggesting that troxerutin could ameliorate skin sensitivity in clinical practice. We concluded that troxerutin is a potential TRPV1 antagonist based on the deep learning MT-DTI model prediction. The present study provides a useful reference for target-based drug discovery using AI technology and may provide useful information for the integrated research field of AI technology and biology.

Virtual and In Vitro Screening of Natural Products Identifies Indole and Benzene Derivatives as Inhibitors of SARS-CoV-2 Main Protease (Mpro).

The rapid spread of the coronavirus disease 2019 (COVID-19) resulted in serious health, social, and economic consequences. While the development of effective vaccines substantially reduced the severity of symptoms and the associated deaths, we still urgently need effective drugs to further reduce the number of casualties associated with SARS-CoV-2 infections. Machine learning methods both improved and sped up all the different stages of the drug discovery processes by performing complex analyses with enormous datasets. Natural products (NPs) have been used for treating diseases and infections for thousands of years and represent a valuable resource for drug discovery when combined with the current computation advancements. Here, a dataset of 406,747 unique NPs was screened against the SARS-CoV-2 main protease (Mpro) crystal structure (6lu7) using a combination of ligand- and structural-based virtual screening. Based on 1) the predicted binding affinities of the NPs to the Mpro, 2) the types and number of interactions with the Mpro amino acids that are critical for its function, and 3) the desirable pharmacokinetic properties of the NPs, we identified the top 20 candidates that could potentially inhibit the Mpro protease function. A total of 7 of the 20 top candidates were subjected to in vitro protease inhibition assay and 4 of them (4/7; 57%), including two beta carbolines, one N-alkyl indole, and one Benzoic acid ester, had significant inhibitory activity against Mpro protease. These four NPs could be developed further for the treatment of COVID-19 symptoms.

CNN-OSBO Encoder-Decoder Architecture for Drug-Target Interaction (DTI) Prediction of Covid-19 Targets

Drug Target Interaction (DTI) prediction is an important factor is drug discovery and repositioning (DDR) since it detects the response of a drug over a target protein. The Coronavirus disease 2019 (COVID-19) disease created groups of deadly pneumonia with clinical appearance mostly similar to SARS-CoV. The precise diagnosis of COVID-19 clinical outcome is more challenging, since the diseases has various forms with varying structures. So predicting the interactions between various drugs with the SARS-CoV target protein is very crucial need in these days, which may leads to discovery of new drugs for the deadly disease. Recently, Deep learning (DL) techniques have been applied by the researches for DTI prediction. Since CNN is one of the major DL models which has the ability to create predictive feature vectors or embeddings, CNN-OSBO encoder-decoder architecture for DTI prediction of Covid-19 targets has been designed Given the input drug and Covid-19 target pair of data, they are fed into the Convolution Neural Networks (CNN) with Opposition based Satin Bowerbird Optimizer (OSBO) encoder modules, separately. Here OSBO is utilized for regulating the hyper parameters (HPs) of CNN layers. Both the encoded data are then embedded to create a binding module. Finally the CNN Decoder module predicts the interaction of drugs over the Covid-19 targets by returning an affinity or interaction score. Experimental results state that DTI prediction using CNN+OSBO achieves better accuracy results when compared with the existing techniques. © 2022 IEEE.

Deep learning optimization for drug-target interaction prediction in COVID-19 using graphic processing unit

The exponentially increasing bioinformatics data raised a new problem: the computation time length. The amount of data that needs to be processed is not matched by an increase in hardware performance, so it burdens researchers on computation time, especially on drug-target interaction prediction, where the computational complexity is exponential. One of the focuses of high-performance computing research is the utilization of the graphics processing unit (GPU) to perform multiple computations in parallel. This study aims to see how well the GPU performs when used for deep learning problems to predict drug-target interactions. This study used the gold-standard data in drug-target interaction (DTI) and the coronavirus disease (COVID-19) dataset. The stages of this research are data acquisition, data preprocessing, model building, hyperparameter tuning, performance evaluation and COVID-19 dataset testing. The results of this study indicate that the use of GPU in deep learning models can speed up the training process by 100 times. In addition, the hyperparameter tuning process is also greatly helped by the presence of the GPU because it can make the process up to 55 times faster. When tested using the COVID-19 dataset, the model showed good performance with 76% accuracy, 74% F-measure and a speed-up value of 179. © 2023 Institute of Advanced Engineering and Science. All rights reserved.

Towards De Novo Drug Design for the Coronavirus: A Drug-Target Interaction Prediction Approach using Atom-enhanced Graph Neural Network with Multi-hop Gating Mechanism

For humans, the COVID-19 pandemic and Coronavirus have undeniably been a nightmare. Although there are effective vaccines, specific drugs are still urgent. Normally, to identify potential drugs, one needs to design and then test interactions between the drug and the virus in an in silico manner for determining candidates. This Drug-Target Interaction (DTI) process, can be done by molecular docking, which is too complicated and time-consuming for manual works. Therefore, it opens room for applying Artificial Intelligence (AI) techniques. In particular, Graph Neural Network (GNN) attracts recent attention since its high suitability for the nature of drug compounds and virus proteins. However, to introduce such a representation well-reflecting biological structures of biological compounds is not a trivial task. Moreover, since available datasets of Coronavirus are still not highly popular, the recently developed GNNs have been suffering from overfitting on them. We then address those issues by proposing a novel model known as Atom-enhanced Graph Neural Network with Multi-hop Gating Mechanism. On one hand, our model can learn more precise features of compounds and proteins. On the other hand, we introduce a new gating mechanism to create better atom representation from non-neighbor information. Once applying transfer learning from very large databanks, our model enjoys promising performance, especially when experimenting with Coronavirus. © 2022 IEEE.

Ligand Binding Prediction Using Protein Structure Graphs and Residual Graph Attention Networks.

Computational prediction of ligand-target interactions is a crucial part of modern drug discovery as it helps to bypass high costs and labor demands of in vitro and in vivo screening. As the wealth of bioactivity data accumulates, it provides opportunities for the development of deep learning (DL) models with increasing predictive powers. Conventionally, such models were either limited to the use of very simplified representations of proteins or ineffective voxelization of their 3D structures. Herein, we present the development of the PSG-BAR (Protein Structure Graph-Binding Affinity Regression) approach that utilizes 3D structural information of the proteins along with 2D graph representations of ligands. The method also introduces attention scores to selectively weight protein regions that are most important for ligand binding. Results: The developed approach demonstrates the state-of-the-art performance on several binding affinity benchmarking datasets. The attention-based pooling of protein graphs enables identification of surface residues as critical residues for protein-ligand binding. Finally, we validate our model predictions against an experimental assay on a viral main protease (Mpro)-the hallmark target of SARS-CoV-2 coronavirus.

UnbiasedDTI: Mitigating Real-World Bias of Drug-Target Interaction Prediction by Using Deep Ensemble-Balanced Learning.

Drug-target interaction (DTI) prediction through in vitro methods is expensive and time-consuming. On the other hand, computational methods can save time and money while enhancing drug discovery efficiency. Most of the computational methods frame DTI prediction as a binary classification task. One important challenge is that the number of negative interactions in all DTI-related datasets is far greater than the number of positive interactions, leading to the class imbalance problem. As a result, a classifier is trained biased towards the majority class (negative class), whereas the minority class (interacting pairs) is of interest. This class imbalance problem is not widely taken into account in DTI prediction studies, and the few previous studies considering balancing in DTI do not focus on the imbalance issue itself. Additionally, they do not benefit from deep learning models and experimental validation. In this study, we propose a computational framework along with experimental validations to predict drug-target interaction using an ensemble of deep learning models to address the class imbalance problem in the DTI domain. The objective of this paper is to mitigate the bias in the prediction of DTI by focusing on the impact of balancing and maintaining other involved parameters at a constant value. Our analysis shows that the proposed model outperforms unbalanced models with the same architecture trained on the BindingDB both computationally and experimentally. These findings demonstrate the significance of balancing, which reduces the bias towards the negative class and leads to better performance. It is important to note that leaning on computational results without experimentally validating them and by relying solely on AUROC and AUPRC metrics is not credible, particularly when the testing set remains unbalanced.

Improved drug-target interaction prediction with intermolecular graph transformer.

The identification of active binding drugs for target proteins (referred to as drug-target interaction prediction) is the key challenge in virtual screening, which plays an essential role in drug discovery. Although recent deep learning-based approaches achieve better performance than molecular docking, existing models often neglect topological or spatial of intermolecular information, hindering prediction performance. We recognize this problem and propose a novel approach called the Intermolecular Graph Transformer (IGT) that employs a dedicated attention mechanism to model intermolecular information with a three-way Transformer-based architecture. IGT outperforms state-of-the-art (SoTA) approaches by 9.1% and 20.5% over the second best option for binding activity and binding pose prediction, respectively, and exhibits superior generalization ability to unseen receptor proteins than SoTA approaches. Furthermore, IGT exhibits promising drug screening ability against severe acute respiratory syndrome coronavirus 2 by identifying 83.1% active drugs that have been validated by wet-lab experiments with near-native predicted binding poses. Source code and datasets are available at https://github.com/microsoft/IGT-Intermolecular-Graph-Transformer.

A Novel Deep Neural Network Technique for Drug-Target Interaction.

Drug discovery (DD) is a time-consuming and expensive process. Thus, the industry employs strategies such as drug repositioning and drug repurposing, which allows the application of already approved drugs to treat a different disease, as occurred in the first months of 2020, during the COVID-19 pandemic. The prediction of drug-target interactions is an essential part of the DD process because it can accelerate it and reduce the required costs. DTI prediction performed in silico have used approaches based on molecular docking simulations, including similarity-based and network- and graph-based ones. This paper presents MPS2IT-DTI, a DTI prediction model obtained from research conducted in the following steps: the definition of a new method for encoding molecule and protein sequences onto images; the definition of a deep-learning approach based on a convolutional neural network in order to create a new method for DTI prediction. Training results conducted with the Davis and KIBA datasets show that MPS2IT-DTI is viable compared to other state-of-the-art (SOTA) approaches in terms of performance and complexity of the neural network model. With the Davis dataset, we obtained 0.876 for the concordance index and 0.276 for the MSE; with the KIBA dataset, we obtained 0.836 and 0.226 for the concordance index and the MSE, respectively. Moreover, the MPS2IT-DTI model represents molecule and protein sequences as images, instead of treating them as an NLP task, and as such, does not employ an embedding layer, which is present in other models.

Discovering missing edges in drug-protein networks: Repurposing drugs for SARS-CoV-2

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, led to a global health crisis, with more than 157 million cases confirmed infected by May 2021. Effective medication is desperately needed. Predicting drug-target interaction (DTI) is an important step to discover novel uses of chemical structures. Here, we develop a pipeline to predict novel DTIs based on the proteins of the coronavirus. Different datasets (human/SARSCoV-2 Protein-Protein interaction (PPI), Drug-Drug similarity (DD sim), and DTIs) are used and combined. After mapping all datasets onto a heterogeneous graph, path-related features are extracted. We then applied various machine learning (ML) algorithms to model our dataset and predict novel DTIs among unlabeled pairs. Possible drugs identified by the models with a high frequency are reported. In addition, evidence of the efficiency of the predicted medicines by the models against COVID-19 are presented. The proposed model can then be generalized to contain other features that provide a context to predict medicine for different diseases. © 2021 IEEE.

Discovering DTI and DDI by Knowledge Graph with MHRW and Improved Neural Network

Drug discovery is of great significance in medical and biological research, while the study of Drug-Target Interaction (DTI) and Drug-Drug Interaction (DDI) can help accelerate drug discovery progress. This paper proposes a new hybrid method for DTI prediction and DDI prediction, which is called MHRW2Vec-TBAN that combines graph representation learning and neural network. MHRW2VecTBAN first constructs knowledge graph KG-DTI and KG-DDI that integrate data related to drugs and targets. Then, an improved graph representation learning model, MHRW2Vec model, is used to obtain feature vectors of reflecting the network structure information for improving the performance of representation learning. Finally, the feature vectors obtained are input to the improved neural network model TextCNN-BiLSTM-Attention Network (TBAN). The experimental results show that, compared with other existing methods, our method could discover more deeper the relationship between drugs and their potential neighborhoods, and has great improvements in DTI prediction and DDI prediction. In addition, the case study of prediction COVID-19 DTI also shows that the proposed model has the potential for actual drug discovery. © 2021 IEEE.

In Silico Prediction of Indonesian Herbs Compounds as Covid-19 Supportive Therapy using Support Vector Machine

Many kinds of research on drug discovery using computational or in silico methods have been carried out. In this era of the Covid-19 pandemic, this research was also carried out by utilizing a commonly used technique, namely using machine learning to predict the interaction of compounds and proteins. This technique is known as Drug Target Interaction (DTI). The compounds used are herbal originating from Indonesia, and the protein used is a potential Covid-19 protein, one of which is SARS-CoV-2. The prediction process with machine learning can only be done on structured data. The data on herbal and protein were processed in this research using the Fingerprint as a descriptor compound and Pseudo Amino Acid Composition (PseAAC) as a protein descriptor technique. The result is structured data processed with the Support Vector Machine algorithm to create an interaction prediction model. The result is that the prediction accuracy is 95.96%. Furthermore, this model can predict Indonesian herbal compounds as drug candidates for Covid-19 supportive therapy. © 2021 IEEE.

DeepH-DTA: Deep Learning for Predicting Drug-Target Interactions: A Case Study of COVID-19 Drug Repurposing.

The rapid spread of novel coronavirus pneumonia (COVID-19) has led to a dramatically increased mortality rate worldwide. Despite many efforts, the rapid development of an effective vaccine for this novel virus will take considerable time and relies on the identification of drug-target (DT) interactions utilizing commercially available medication to identify potential inhibitors. Motivated by this, we propose a new framework, called DeepH-DTA, for predicting DT binding affinities for heterogeneous drugs. We propose a heterogeneous graph attention (HGAT) model to learn topological information of compound molecules and bidirectional ConvLSTM layers for modeling spatio-sequential information in simplified molecular-input line-entry system (SMILES) sequences of drug data. For protein sequences, we propose a squeezed-excited dense convolutional network for learning hidden representations within amino acid sequences; while utilizing advanced embedding techniques for encoding both kinds of input sequences. The performance of DeepH-DTA is evaluated through extensive experiments against cutting-edge approaches utilising two public datasets (Davis, and KIBA) which comprise eclectic samples of the kinase protein family and the pertinent inhibitors. DeepH-DTA attains the highest Concordance Index (CI) of 0.924 and 0.927 and also achieved a mean square error (MSE) of 0.195 and 0.111 on the Davis and KIBA datasets respectively. Moreover, a study using FDA-approved drugs from the Drug Bank database is performed using DeepH-DTA to predict the affinity scores of drugs against SARS-CoV-2 amino acid sequences, and the results show that that the model can predict some of the SARS-Cov-2 inhibitors that have been recently approved in many clinical studies.

Deep drug-target binding affinity prediction with multiple attention blocks.

Drug-target interaction (DTI) prediction has drawn increasing interest due to its substantial position in the drug discovery process. Many studies have introduced computational models to treat DTI prediction as a regression task, which directly predict the binding affinity of drug-target pairs. However, existing studies (i) ignore the essential correlations between atoms when encoding drug compounds and (ii) model the interaction of drug-target pairs simply by concatenation. Based on those observations, in this study, we propose an end-to-end model with multiple attention blocks to predict the binding affinity scores of drug-target pairs. Our proposed model offers the abilities to (i) encode the correlations between atoms by a relation-aware self-attention block and (ii) model the interaction of drug representations and target representations by the multi-head attention block. Experimental results of DTI prediction on two benchmark datasets show our approach outperforms existing methods, which are benefit from the correlation information encoded by the relation-aware self-attention block and the interaction information extracted by the multi-head attention block. Moreover, we conduct the experiments on the effects of max relative position length and find out the best max relative position length value $k \in \{3, 5\}$. Furthermore, we apply our model to predict the binding affinity of Corona Virus Disease 2019 (COVID-19)-related genome sequences and $3137$ FDA-approved drugs.

PreDTIs: prediction of drug-target interactions based on multiple feature information using gradient boosting framework with data balancing and feature selection techniques.

Discovering drug-target (protein) interactions (DTIs) is of great significance for researching and developing novel drugs, having a tremendous advantage to pharmaceutical industries and patients. However, the prediction of DTIs using wet-lab experimental methods is generally expensive and time-consuming. Therefore, different machine learning-based methods have been developed for this purpose, but there are still substantial unknown interactions needed to discover. Furthermore, data imbalance and feature dimensionality problems are a critical challenge in drug-target datasets, which can decrease the classifier performances that have not been significantly addressed yet. This paper proposed a novel drug-target interaction prediction method called PreDTIs. First, the feature vectors of the protein sequence are extracted by the pseudo-position-specific scoring matrix (PsePSSM), dipeptide composition (DC) and pseudo amino acid composition (PseAAC); and the drug is encoded with MACCS substructure fingerings. Besides, we propose a FastUS algorithm to handle the class imbalance problem and also develop a MoIFS algorithm to remove the irrelevant and redundant features for getting the best optimal features. Finally, balanced and optimal features are provided to the LightGBM Classifier to identify DTIs, and the 5-fold CV validation test method was applied to evaluate the prediction ability of the proposed method. Prediction results indicate that the proposed model PreDTIs is significantly superior to other existing methods in predicting DTIs, and our model could be used to discover new drugs for unknown disorders or infections, such as for the coronavirus disease 2019 using existing drugs compounds and severe acute respiratory syndrome coronavirus 2 protein sequences.

Deep Learning-Based Potential Ligand Prediction Framework for COVID-19 with Drug-Target Interaction Model.

To fight against the present pandemic scenario of COVID-19 outbreak, medication with drugs and vaccines is extremely essential other than ventilation support. In this paper, we present a list of ligands which are expected to have the highest binding affinity with the S-glycoprotein of 2019-nCoV and thus can be used to make the drug for the novel coronavirus. Here, we implemented an architecture using 1D convolutional networks to predict drug-target interaction (DTI) values. The network was trained on the KIBA (Kinase Inhibitor Bioactivity) dataset. With this network, we predicted the KIBA scores (which gives a measure of binding affinity) of a list of ligands against the S-glycoprotein of 2019-nCoV. Based on these KIBA scores, we are proposing a list of ligands (33 top ligands based on best interactions) which have a high binding affinity with the S-glycoprotein of 2019-nCoV and thus can be used for the formation of drugs.