Abstract

Drug discovery is a long, expensive, and extremely laborious process that involves multiple steps with knowledge from a wide variety of domains like chemistry, biology and pharmacology. The first step in this process is the identification of potential hit molecules for a novel target followed by experimental evaluation typically using biochemical assays toward lead identification. These hits are then optimized to have higher binding affinity, low toxicity, and improved bioavailability among other requirements. The time and expense involved in this process has given rise to alternate in silico approaches like virtual screening wherein molecules are computationally evaluated to identify potential hits. The structure based drug design (SBDD) method, docking, is used most commonly in virtual screening to identify molecules with high binding affinity to the given target (1–

Abstract

The discovery of new molecules and materials helps expand the horizons of novel and innovative real-life applications. In pursuit of finding molecules with desired properties, chemists have traditionally relied on experimentation and recently on combinatorial methods to generate new substances often complimented by computational methods. The sheer size of the chemical space makes it infeasible to search through all possible molecules exhaustively. This calls for fast and efficient methods to navigate the chemical space to find substances with desired properties. This class of problems is referred to as inverse design problems. There are a variety of inverse problems in chemistry encompassing various subfields like drug discovery, retrosynthesis, structure identification, etc. Recent developments in modern machine learning (ML) methods have shown great promise in tackling problems of this kind. This has …

Abstract

Application of deep learning techniques for de novo generation of molecules, termed as inverse molecular design, has been gaining enormous traction in drug design. The representation of molecules in SMILES notation as a string of characters enables the usage of state of the art models in natural language processing, such as Transformers, for molecular design in general. Inspired by generative pre-training (GPT) models that have been shown to be successful in generating meaningful text, we train a transformer-decoder on the next token prediction task using masked self-attention for the generation of druglike molecules in this study. We show that our model, MolGPT, performs on par with other previously proposed modern machine learning frameworks for molecular generation in terms of generating valid, unique, and novel molecules. Furthermore, we demonstrate that the model can be trained conditionally to

Abstract

Pattern mining from graph transactional data (GTD) is an active area of research with applications in the domains of bioinformatics, chemical informatics and social networks. Existing works address the problem of mining frequent subgraphs from GTD. However, the knowledge concerning the coverage aspect of a set of subgraphs is also valuable for improving the performance of several applications. In this regard, we introduce the notion of subgraph coverage patterns (SCPs). Given a GTD, a subgraph coverage pattern is a set of subgraphs subject to relative frequency, coverage and overlap constraints provided by the user. We propose the Subgraph ID-based Flat Transactional (SIFT) framework for the efficient extraction of SCPs from a given GTD. Our performance evaluation using three real datasets demonstrates that our proposed SIFT framework is indeed capable of efficiently extracting SCPs from GTD. Furthermore, we demonstrate the effectiveness of SIFT through a case study in computer-aided drug design.

Abstract

Nucleocytoplasmic shuttling of viral elements, supported by several host factors, is essential for the replication of the human immunodeficiency virus (HIV). HIV-1 uses a nuclear RNA export pathway mediated by viral protein Rev to transport its Rev response element (RRE)-containing partially spliced and unspliced transcripts aided by the host nuclear RNA export protein CRM1. The factor(s) interacting with the CRM1-Rev complex are potential antiretroviral target(s) and could serve as a retroviral model system to study nuclear export machinery adapted by these viruses. We earlier reported that cellular Staufen-2 interacts with Rev, facilitating viral-RNA export. Here, we identified the formation of a complex between Staufen-2, CRM1 and Rev. Molecular docking and simulations mapped the interacting residues in the RNA-binding Domain 4 of Staufen-2 as R336 and R337, which were experimentally verified to be critical for interactions among Staufen-2, CRM1 and Rev by mutational analysis. Staufen-2 mutants defective in interaction with CRM1 or Rev failed to supplement the Rev-RNA export activity and viral production, demonstrating the importance of these interactions. Rev-dependent reporter assays and proviral DNA-construct transfection-based studies in Staufen-2 knockout cells in the presence of leptomycin-B (LMB) revealed a significant reduction in CRM1-mediated Rev-dependent RNA export with decreased virus production as compared to Staufen-2 knockout background or LMB treatment alone, suggesting the relevance of these interactions in augmenting RNA export activity of Rev. Our observations provide further insights into the mechanistic intricacies of unspliced viral-RNA export to the cytoplasm and support the notion that abrogating such interactions can reduce HIV-1 proliferation.

Abstract

In this work, we describe an end-to-end deep learning architecture for Heart Murmur Detection from Phonocardiogram(PCG) recordings as part of The George B. Moody PhysioNet Challenge 2022. Our team, “Team IIITH” received a weighted accuracy score of 0.708 (ranked 19th out of 40 teams) and Challenge cost of 13264 (ranked 22nd out of 39 teams) on the official hidden test set. In our approach, the PCG recordings are first downsampled to 1000 Hz before being passed through a Butterworth’s low and high pass filter to remove baseline wanders and high-frequency noise present in the recordings. The PCG recordings are then broken down into 10-second segments and normalized to bring all trainable samples to the same size. To extract embeddings more efficiently, we built a custom 1-dimensional Residual Network (ResNet) where the 10-second inputs are passed through variable-sized kernel ResNets in parallel, before being concatenated and passed through the next ResNet layer to account for different length dependencies across the PCG signal. The output of this custom ResNet is then fed to a 2-layer feed-forward network for final classification. Cross-Entropy Loss with class weights was employed to account for class imbalance. Our approach obtained a 5-fold Cross-Validation weighted accuracy score of 0.71 and challenge cost score of 12067 on the training set.

Abstract

In this work, we describe an end-to-end deep learning architecture for Heart Murmur Detection from Phonocardiogram(PCG) recordings as part of The George B. Moody PhysioNet Challenge 2022. Our team, “Team IIITH” received a weighted accuracy score of 0.708 (ranked 19th out of 40 teams) and Challenge cost of 13264 (ranked 22nd out of 39 teams) on the official hidden test set. In our approach, the PCG recordings are first downsampled to 1000 Hz before being passed through a Butterworth’s low and high pass filter to remove baseline wanders and high-frequency noise present in the recordings. The PCG recordings are then broken down into 10-second segments and normalized to bring all trainable samples to the same size. To extract embeddings more efficiently, we built a custom 1-dimensional Residual Network (ResNet) where the 10-second inputs are passed through variable-sized kernel ResNets in parallel, before being concatenated and passed through the next ResNet layer to account for different length dependencies across the PCG signal. The output of this custom ResNet is then fed to a 2-layer feed-forward network for final classification. Cross-Entropy Loss with class weights was employed to account for class imbalance. Our approach obtained a 5-fold Cross-Validation weighted accuracy score of 0.71 and challenge cost score of 12067 on the training set

Abstract

Machine learning (ML) methods enable computers to address problems by learning from existing data. Such applications are becoming commonplace in molecular sciences. Interest in applying ML techniques across chemical compound space, from predicting properties to designing molecules and materials is in the surge. Especially, ML models have started to accelerate computational chemistry, and are often as accurate as state‐of‐the‐art electronic/atomistic models. Being an integral part of the ML architecture, representation of a molecular entity, uniquely encoded, plays a crucial role to what extent an ML model would be accurately predicting the desired property. This review aims to demonstrate a hierarchy of representations which has been introduced, to capture all degrees of freedom of a molecule or an atom the best, to map the quantum mechanical properties. We discuss their diverse applications how …

Abstract

The coronavirus disease 2019 (COVID-19), caused by the virus SARS-CoV-2, is an acute respiratory disease that has been classified as a pandemic by the World Health Organization (WHO). The sudden spike in the number of infections and high mortality rates have put immense pressure on the public healthcare systems. Hence, it is crucial to identify the key factors for mortality prediction to optimize patient treatment strategy. Different routine blood test results are widely available compared to other forms of data like X-rays, CT-scans, and ultrasounds for mortality prediction. This study proposes machine learning (ML) methods based on blood tests data to predict COVID-19 mortality risk. A powerful combination of five features: neutrophils, lymphocytes, lactate dehydrogenase (LDH), high-sensitivity C-reactive protein (hs-CRP), and age helps to predict mortality with 96% accuracy. Various ML models (neural networks, logistic regression, XGBoost, random forests, SVM, and decision trees) have been trained and performance compared to determine the model that achieves consistently high accuracy across the days that span the disease. The best performing method using XGBoost feature importance and neural network classification, predicts with an accuracy of 90% as early as 16 days before the outcome. Robust testing with three cases based on days to outcome confirms the strong predictive performance and practicality of the proposed model. A detailed analysis and identification of trends was performed using these key biomarkers to provide useful insights for intuitive application. This study provide solutions that would help accelerate the decision-making process in healthcare systems for focused medical treatments in an accurate, early, and reliable manner

Abstract

Energetically unfavorable Watson–Crick (WC)-like tautomeric forms of nucleobases are known to introduce spontaneous mutations, and contribute to replication, transcription, and translation errors. Recent NMR relaxation dispersion techniques were able to show that wobble (w) G•U mispair exists in equilibrium with the short-lived, low-population WC-like enolic tautomers. Presently, we have investigated the wG•U → WC-like enolic reaction pathway using various theoretical methods: quantum mechanics (QM), molecular dynamics (MD), and combined quantum mechanics/molecular mechanics (QM/MM). The previous studies on QM gas phase calculations were inconsistent with experimental data. We have also explored the environmental effects on the reaction energies by adding explicit water. While the QM-profile clearly becomes endoergic in the presence of water, the QM/MM-profile remains consistently endoergic in the presence and absence of water. Hence, by including microsolvation and QM/MM calculations, the experimental data can be explained. For the G•Uenol → Genol•U pathway, the latter appears to be energetically more favorable throughout all computational models. This study can be considered as a benchmark of various computational models of wG•U to WC-like tautomerization pathways with and without the environmental effects, and may contribute on further studies of other mispairs as well.