Artificial intelligence (AI)/machine learning (ML) is emerging as pivotal in synthetic chemistry, offering revolutionary potential in retrosynthetic analysis, reaction conditions and reaction prediction. We have combined chemical descriptors, primarily based on Density Functional Theory (DFT) calculations, with various AI/ML tools such as Multi-Layer Perceptron (MLP) and Random Forest (RF), to predict the synthesis of 2-arylbenzothiazole in photoredox reactions. Significantly, our models underscore the critical role of the molecular structure and physicochemical characteristics of the base, especially the total atomic polarizabilities, in the rate-determining steps involving cyclohexyl and phenethyl moieties of the substrate.
View Article and Find Full Text PDFVirtual screening (VS) has been incorporated into the paradigm of modern drug discovery. This field is now undergoing a new wave of revolution driven by artificial intelligence and more specifically, machine learning (ML). In terms of those out-of-the-box datasets for model training or benchmarking, their data volume and applicability domain are limited.
View Article and Find Full Text PDFMachine learning (ML) has been used to build high-performance prediction models in the past without considering race. African Americans (AA) are vulnerable to acute kidney injury (AKI) at a higher eGFR level than Caucasians. AKI increases mortality, length of hospital stays, and incidence of chronic kidney disease (CKD) and end-stage renal disease (ESRD).
View Article and Find Full Text PDFExpert Opin Drug Discov
October 2021
: Structure-based virtual screening (SBVS) is an essential strategy for hit identification. SBVS primarily uses molecular docking, which exploits the protein-ligand binding mode and associated affinity score for compound ranking. Previous studies have shown that computational representation of protein-ligand interfaces and the later establishment of machine learning models are efficacious in improving the accuracy of SBVS.
View Article and Find Full Text PDFCC chemokine receptor 2 (CCR2) antagonists that disrupt CCR2/MCP-1 interaction are expected to treat a variety of inflammatory and autoimmune diseases. The lack of CCR2 crystal structure limits the application of structure-based drug design (SBDD) to this target. Although a few three-dimensional theoretical models have been reported, their accuracy remains to be improved in terms of templates and modeling approaches.
View Article and Find Full Text PDFFarnesoid X receptor (FXR) agonists can reverse dysregulated bile acid metabolism, and thus, they are potential therapeutics to prevent and treat nonalcoholic fatty liver disease. The low success rate of FXR agonists' R&D and the side effects of clinical candidates such as obeticholic acid make it urgent to discover new chemotypes. Unfortunately, structure-based virtual screening (SBVS) that can speed up drug discovery has rarely been reported with success for FXR, which was likely hindered by the failure in addressing protein flexibility.
View Article and Find Full Text PDFLigand enrichment assessment based on benchmarking data sets has become a necessity for the rational selection of the best-suited approach for prospective data mining of drug-like molecules. Up to now, a variety of benchmarking data sets had been generated and frequently used. Among them, MUBD-HDACs from our prior research efforts was regarded as one of five state-of-the-art benchmarks in 2017 by Frontiers in Pharmacology.
View Article and Find Full Text PDFMath Biosci Eng
March 2019
In this paper, we propose a diffusive epidemic model with a standard incidence rate and distributed delays in disease transmission. We also consider the degenerate case when one of the diffusion coe cients vanishes. By establishing existence theory of traveling wave solutions and providing sharp lower bound for the wave speeds, we prove linear determinacy of the proposed model system.
View Article and Find Full Text PDFProtein tyrosine phosphatase 1B (PTP1B) has recently been identified as a potential target of Norathyriol. Unfortunately, Norathyriol is not a potent PTP1B inhibitor, which somewhat hinders its further application. Based on the fact that no study on the relationship of chemical structure and PTP1B inhibitory activity of Norathyriol has been reported so far, we attempted to perform structural optimization so as to improve the potency for PTP1B.
View Article and Find Full Text PDFChemokine receptors (CRs) have long been druggable targets for the treatment of inflammatory diseases and HIV-1 infection. As a powerful technique, virtual screening (VS) has been widely applied to identifying small molecule leads for modern drug targets including CRs. For rational selection of a wide variety of VS approaches, ligand enrichment assessment based on a benchmarking data set has become an indispensable practice.
View Article and Find Full Text PDFQuionolone carboxylic acid derivatives as inhibitors of HIV-1 integrase were investigated as a potential class of drugs for the treatment of acquired immunodeficiency syndrome (AIDS). Hologram quantitative structure-activity relationships (HQSAR) and translocation comparative molecular field vector analysis (topomer CoMFA) were applied to a series of 48 quionolone carboxylic acid derivatives. The most effective HQSAR model was obtained using atoms and bonds as fragment distinctions: cross-validation = 0.
View Article and Find Full Text PDFJ Enzyme Inhib Med Chem
December 2018
Histone deacetylase 3 (HDAC3) is a potential target for the treatment of human diseases such as cancers, diabetes, chronic inflammation and neurodegenerative diseases. Previously, we proposed a virtual screening (VS) pipeline named "Hypo1_FRED_SAHA-3" for the discovery of HDAC3 inhibitors (HDAC3Is) and had thoroughly validated it by theoretical calculations. In this study, we attempted to explore its practical utility in a large-scale VS campaign.
View Article and Find Full Text PDFInhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson's disease), stroke, and sepsis.
View Article and Find Full Text PDFStructure-based virtual screening (SBVS) has become an indispensable technique for hit identification at the early stage of drug discovery. However, the accuracy of current scoring functions is not high enough to confer success to every target and thus remains to be improved. Previously, we had developed binary pose filters (PFs) using knowledge derived from the protein-ligand interface of a single X-ray structure of a specific target.
View Article and Find Full Text PDFHistone deacetylase 3 (HDAC3) has been recently identified as a potential target for the treatment of cancer and other diseases, such as chronic inflammation, neurodegenerative diseases, and diabetes. Virtual screening (VS) is currently a routine technique for hit identification, but its success depends on rational development of VS strategies. To facilitate this process, we applied our previously released benchmarking dataset, i.
View Article and Find Full Text PDFLigand based virtual screening (LBVS) approaches could be broadly divided into those relying on chemical similarity searches and those employing Quantitative Structure-Activity Relationship (QSAR) models. We have compared the predictive power of these approaches using some datasets of compounds tested against several G-Protein Coupled Receptors (GPCRs). The k-Nearest Neighbors (kNN) QSAR models were built for known ligands of each GPCR target independently, with a fraction of tested ligands for each target set aside as a validation set.
View Article and Find Full Text PDFComb Chem High Throughput Screen
May 2016
Histone deacetylases (HDACs) are part of a vast family of enzymes with crucial roles in numerous biological processes, largely through their repressive influence on transcription, with serious implications in a variety of human diseases. Among different isoforms, human HDAC2 in particular draws attention as a promising target for the treatment of cancer and memory deficits associated with neurodegenerative diseases. Now the challenge is to obtain a compound that is structurally novel and truly selective to HDAC2 because most current HDAC2 inhibitors do not show isoforms selectivity and suffer from metabolic instability.
View Article and Find Full Text PDFThe human 5-hydroxytryptamine receptor subtype 1A (5-HT1A) is highly expressed in the raphe nuclei region and limbic structures; for that reason 5-HT1A has served as a promising target for treating human mood disorders and neurodegenerative diseases. We have developed binary quantitative structure-activity relationship (QSAR) models for 5- HT1A binding using data retrieved from the WOMBAT database and the k-Nearest Neighbor (kNN) machine learning method. A rigorous QSAR modeling and screening workflow had been followed, with extensive internal and external validation processes.
View Article and Find Full Text PDFHistone deacetylases (HDACs) are an important class of drug targets for the treatment of cancers, neurodegenerative diseases, and other types of diseases. Virtual screening (VS) has become fairly effective approaches for drug discovery of novel and highly selective histone deacetylase inhibitors (HDACIs). To facilitate the process, we constructed maximal unbiased benchmarking data sets for HDACs (MUBD-HDACs) using our recently published methods that were originally developed for building unbiased benchmarking sets for ligand-based virtual screening (LBVS).
View Article and Find Full Text PDFRetrospective small-scale virtual screening (VS) based on benchmarking data sets has been widely used to estimate ligand enrichments of VS approaches in the prospective (i.e. real-world) efforts.
View Article and Find Full Text PDFRecent Pat Drug Deliv Formul
June 2015
Nanoformulations (NF) are widely explored as potential alternatives for traditional ophthalmic formulation approaches. The effective treatment of ocular diseases using conventional eye drops is often hampered by factors such as: physiological barriers, rapid elimination, protein binding, and enzymatic drug degradation. Combined, these factors are known to contribute to reduced ocular residence time and poor bioavailability.
View Article and Find Full Text PDFBenchmarking data sets have become common in recent years for the purpose of virtual screening, though the main focus had been placed on the structure-based virtual screening (SBVS) approaches. Due to the lack of crystal structures, there is great need for unbiased benchmarking sets to evaluate various ligand-based virtual screening (LBVS) methods for important drug targets such as G protein-coupled receptors (GPCRs). To date these ready-to-apply data sets for LBVS are fairly limited, and the direct usage of benchmarking sets designed for SBVS could bring the biases to the evaluation of LBVS.
View Article and Find Full Text PDFThe 5-hydroxytryptamine 1A (5-HT1A) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia. We have developed binary classification quantitative structure-activity relationship (QSAR) models of 5-HT1A receptor binding activity using data retrieved from the PDSP Ki database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as using an additional validation set comprising 66 structurally distinct compounds from the World of Molecular Bioactivity database.
View Article and Find Full Text PDFSerotonin (5-hydroxytryptamine, 5-HT) receptors are neuromodulator neurotransmitter receptors which when activated trigger a signal transduction cascade within cells resulting in cell-cell communication. 5-hydroxytryptamine receptor 2B (5-HT2B) is a subtype of the seven members of 5-hydroxytrytamine receptors family which is the largest member of the super family of 7-transmembrane G-protein coupled receptors (GPCRs). Not only do 5-HT receptors play physiological roles in the cardiovascular system, gastrointestinal and endocrine function as well as the central nervous system, but they also play a role in behavioral functions.
View Article and Find Full Text PDFStudies of the fracture behavior of cortical bone have determined multiple toughening mechanisms that are active during propagation of a crack. Common methods for measuring bone fracture toughness use single-notched specimens often in four-point (SN4PB) or three-point bending (SN3PB). A double-notch four-point bending (DN4PB) specimen is useful to study prefailure damage at the crack tip.
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