Abstract

There has been tremendous advancement in machine learning (ML) applications in computational chemistry, particularly in neural network potentials (NNP). NNPs can approximate potential energy surface (PES) as a high dimensional function by learning from existing reference data, thereby circumventing the need to solve the electronic Schrödinger equation explicitly. As a result, ML accelerates chemical space exploration and property prediction compared to quantum mechanical methods. Novel ML methods have the potential to provide efficient means for predicting the properties of molecules. However, this potential has been limited by the lack of standard comparative evaluations. In this work, we compare four selected models, that is, ANI, PhysNet, SchNet, and BAND‐NN, developed to represent the PES of small organic molecules. We evaluate these models for their accuracy and transferability on two

Abstract

Protein–drug interactions play important roles in many biological processes and therapeutics. Predicting the binding sites of a protein helps to discover such interactions. New drugs can be designed to optimize these interactions, improving protein function. The tertiary structure of a protein decides the binding sites available to the drug molecule, but the determination of the 3D structure is slow and expensive. Conversely, the determination of the amino acid sequence is swift and economical. Although quick and accurate prediction of the binding site using just the sequence is challenging, the application of Deep Learning, which has been hugely successful in several biochemical tasks, makes it feasible. BiRDS is a Residual Neural Network that predicts the protein’s most active binding site using sequence information. SC-PDB, an annotated database of druggable binding sites, is used for training the network …

Abstract

A system and method for exploring a chemical space during molecular design for at least one top hit molecule using a machine learning (ML) model are provided. The method includes (i) representing the at least one molecule stored in a drug library into at least one vector;(ii) clustering the at least one vector to obtain at least one cluster of molecules into one or more clusters;(iii) uniformly sampling a first subset of molecules from each cluster of molecules;(vi) determining a docking score for sampled subset of molecules;(iv) training the ML model by correlating sampled subset of molecules with docking score;(viii) computing acquisition function values for a second subset of molecules from each cluster; and (ix) determining at least one top hit molecule based on the computed acquisition function values, thereby exploring the chemical space for the at least one top hit molecule.

Abstract

Spectroscopy is the study of how matter interacts with electromagnetic radiation. The spectra of any molecule are highly information-rich, yet the inverse relation of spectra to the corresponding molecular structure is still an unsolved problem. Nuclear magnetic resonance (NMR) spectroscopy is one such critical technique in the scientists’ toolkit to characterize molecules. In this work, a novel machine learning framework is proposed that attempts to solve this inverse problem by navigating the chemical space to find the correct structure given an NMR spectra. The proposed framework uses a combination of online Monte Carlo tree search (MCTS) and a set of graph convolution networks to build a molecule iteratively. Our method can predict the structure of the molecule ∼80% of the time in its top 3 guesses for molecules with <10 heavy atoms. We believe that the proposed framework is a significant step in solving the

Abstract

Ketones are the key functional group that recurs in chemistry and biology, and accessing them through simple and economic ways is highly desirable. Herein, we report the synthesis of unsymmetrical ketones from abundant toluene and alkyl esters, where volatile alcohols are the sole byproduct. This protocol applies to a repertoire of substrates bearing electron‐donating, electron‐withdrawing, and neutral substituents. Most importantly, the organometallic ferrocenyl ester underwent aroylation with ease. This method is the first example to furnish diketones from methyl arenes and diesters. Furthermore, cyclic imide was synthesized by this protocol utilizing KN(SiMe3)2 as a ′nitrogen′ source. Density functional theory studies provide insight into deprotonation of toluene by K+‐π interaction by increasing its acidity, and this being the rate‐determining step.

Abstract

Computational methods and recently modern machine learning methods have played a key role in structure-based drug design. Though several benchmarking datasets are available for machine learning applications in virtual screening, accurate prediction of binding afnity for a protein-ligand complex remains a major challenge. New datasets that allow for the development of models for predicting binding afnities better than the state-of-the-art scoring functions are important. For the frst time, we have developed a dataset, PLAS-5k comprised of 5000 protein-ligand complexes chosen from PDB database. The dataset consists of binding afnities along with energy components like electrostatic, van der Waals, polar and non-polar solvation energy calculated from molecular dynamics simulations using MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. The calculated binding afnities outperformed docking scores and showed a good correlation with the available experimental values. The availability of energy components may enable optimization of desired components during machine learning-based drug design. Further, OnionNet model has been retrained on PLAS-5k dataset and is provided as a baseline for the prediction of binding afnities

Abstract

A unique B–N coordinated phenanthroimidazole-based zinc salen was synthesized. The zinc salen thus synthesized acts as a photocatalyst for the cycloaddition of carbon dioxide with terminal epoxides under ambient conditions. DFT study of the cycloaddition of carbon dioxide with terminal epoxide indicates the preference of the reaction pathway when photocatalyzed by zinc salen. We anticipate that this strategy will help to design new photocatalysts for CO2 fixation.

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 …

Abstract

The variability of clinical course and prognosis of COVID-19 highlights the necessity of patient sub-group risk stratification based on clinical data. In this study, clinical data from a cohort of Indian COVID-19 hospitalized patients is used to develop risk stratification and mortality prediction models. We analyzed a set of 70 clinical parameters including physiological and hematological for developing machine learning models to identify biomarkers. We also compared the Indian and Wuhan cohort, and analyzed the role of steroids. A bootstrap averaged ensemble of Bayesian networks was also learned to construct an explainable model for discovering actionable influences on mortality and days to outcome. We discovered blood parameters, diabetes, co-morbidity and SpO2 levels as important risk stratification features, whereas mortality prediction is dependent only on blood parameters. XGboost and logistic regression model yielded the best performance on risk stratification and mortality prediction, respectively (AUC score 0.83, AUC score 0.92). Blood coagulation parameters (ferritin, D-Dimer and INR), immune and inflammation parameters IL6, LDH and Neutrophil (%) are common features for both risk and mortality prediction. Compared with Wuhan patients, Indian patients with extreme blood parameters indicated higher survival rate. Analyses of medications suggest that a higher proportion of survivors and mild patients who were administered steroids had extreme neutrophil and lymphocyte percentages. The ensemble averaged Bayesian network structure revealed serum ferritin to be the mos

Abstract

The current global health emergency in the form of the Coronavirus 2019 (COVID-19) pandemic has 16 highlighted the need for fast, accurate, and efficient drug discovery pipelines. Traditional drug 17 discovery projects relying on in vitro high-throughput screening (HTS) involve large investments and 18 sophisticated experimental set-ups, affordable only to big biopharmaceutical companies. In this 19 scenario, application of efficient state-of-the-art computational methods and modern artificial 20 intelligence (AI)-based algorithms for rapid screening of repurposable chemical space [approved drugs 21 and natural products (NPs) with proven pharmacokinetic profiles] to identify the initial leads is a 22 powerful option to save resources and time. Structure-based drug repurposing is a popular in silico 23 repurposing approach. In this review, we discuss traditional and modern AI-based computational 24 methods and tools applied at various stages for structure-based drug discovery (SBDD) pipelines. 25 Additionally, we highlight the role of generative m