A5051906581- Computational Drug Discovery Methods
- Liver Disease Diagnosis and Treatment
- Metabolomics and Mass Spectrometry Studies
- Estrogen and related hormone effects
- Pharmacogenetics and Drug Metabolism
- Liver physiology and pathology
- Inflammatory mediators and NSAID effects
- Acute Kidney Injury Research
- Renal Transplantation Outcomes and Treatments
- Chronic Kidney Disease and Diabetes
- Protein Kinase Regulation and GTPase Signaling
- Drug Transport and Resistance Mechanisms
- Carcinogens and Genotoxicity Assessment
- Analytical Chemistry and Chromatography
- Synthesis and biological activity
- Biochemical and Molecular Research
- Bacillus and Francisella bacterial research
- PI3K/AKT/mTOR signaling in cancer
- Gene expression and cancer classification
- Heavy Metal Exposure and Toxicity
- Cholinesterase and Neurodegenerative Diseases
- Drug-Induced Hepatotoxicity and Protection
- Monoclonal and Polyclonal Antibodies Research
- Microbial Natural Products and Biosynthesis
- Machine Learning in Materials Science
United States Army Medical Research and Development Command
2015-2025
Telemedicine & Advanced Technology Research Center
2015-2025
Henry M. Jackson Foundation
2019-2025
Defense Health Agency
2025
University of Kentucky
2006-2014
United States Department of the Army
2011-2013
Transylvania University
2010
Polypharmacology has emerged as a new theme in drug discovery. In this paper, we studied polypharmacology using ligand-based target fishing (LBTF) protocol. To implement the protocol, first generated chemogenomic database that links individual protein targets with specified set of drugs or representatives. Target profiles were then for given query molecule by computing maximal shape/chemistry overlap between and sets assigned to each target. The was computed program ROCS (Rapid Overlay...
Toxic liver injury causes necrosis and fibrosis, which may lead to cirrhosis failure. Despite recent progress in understanding the mechanism of our knowledge molecular-level details this disease is still incomplete. The elucidation networks pathways associated with fibrosis can provide insight into underlying molecular mechanisms disease, as well identify potential diagnostic or prognostic biomarkers. Towards end, we analyzed rat gene expression data from a range chemical exposures that...
3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a promising target for developing novel anticancer drugs. In order to understand the structure−activity correlation of indolinone-based PDK1 inhibitors, we have carried out combined molecular docking and three-dimensional quantitative relationship (3D-QSAR) modeling study. The study has resulted in two types satisfactory 3D-QSAR models, including CoMFA model (r2 = 0.907; q2 0.737) CoMSIA 0.991; 0.824), predicting biological activity new...
The expanded use of multiple drugs has increased the occurrence adverse drug reactions (ADRs) induced by drug-drug interactions (DDIs). However, such are typically not observed in clinical drug-development studies because most them focus on single-drug therapies. ADR reporting systems collect information health effects caused both single and DDIs. A major challenge is to unambiguously identify DDIs attribute specific interactions. computational method that provides prospective predictions...
Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due their association multiple diseases organ injuries. Per- polyfluoro alkyl substances (PFAS) polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that associated steatosis liver. Although PFAS PAH classified as molecular mechanisms toxicity remain be explored detail. In this study, we aimed identify by which an acute exposure can induce lipid...
Microsomal prostaglandin E synthase-1 (mPGES-1) is an essential enzyme involved in a variety of diseases and the most promising target for design next-generation anti-inflammatory drugs. In order to establish solid structural base, we recently developed model mPGES-1 trimer structure by using available crystal structures both microsomal glutathione transferase-1 (MGST1) ba3-cytochrome c oxidase as templates. The has been used present study examine detailed binding with substrate PGH2...
As novel and drug-resistant bacterial strains continue to present an emerging health threat, the development of new antibacterial agents is critical. This includes making improvements existing scaffolds as well identifying ones. The aim this study apply a Bayesian classification QSAR approach rapidly screen chemical libraries for compounds predicted have activity. Toward end we assembled data set 317 known second diverse, well-validated, non-antibacterial from 215 PubChem Bioassays against...
Toxic industrial chemicals induce liver injury, which is difficult to diagnose without invasive procedures. Identifying indicators of end organ injury can complement exposure-based assays and improve predictive power. A multiplexed approach was used experimentally evaluate a panel 67 genes predicted be associated with the fibrosis pathology by computationally mining DrugMatrix, publicly available repository gene microarray data. Five-day oral gavage studies in male Sprague Dawley rats dosed...
Transporters are membrane proteins that critical for normal cellular function and mediate the transport of endogenous exogenous chemicals. Chemical interactions with these transporters have potential to affect pharmacokinetic properties drugs. Inhibition can cause adverse drug-drug toxicity, whereas if a drug is substrate transporter, it could lead reduced therapeutic effects. The importance in efficacy toxicity has led regulatory agencies, such as U.S. Food Drug Administration European...
Abstract Muscarinic receptor subtype 1 (M1) is a G protein-coupled (GPCR) and key pharmacological target for peripheral neuropathy, chronic obstructive pulmonary disease, nerve agent exposures, cognitive disorders. Screening identifying compounds with potential to interact M1 will aid in rational drug design these In this work, we developed machine learning-based classification models utilizing publicly available bioactivity data. As inactive are rarely reported the literature, encountered...
Liver injuries due to ingestion or exposure chemicals and industrial toxicants pose a serious health risk that may be hard assess lack of non-invasive diagnostic tests. Mapping chemical organ-specific damage clinical outcomes via biomarkers biomarker panels will provide the foundation for highly specific robust Here, we have used DrugMatrix, toxicogenomics database containing gene expression data matched dose-dependent exposures adverse pathology assessments in Sprague Dawley rats, identify...
Exposure to chemicals contributes the development and progression of fatty liver, or steatosis, a process characterized by abnormal accumulation lipids within liver cells. However, lack knowledge on how cause steatosis has prevented any large-scale assessment 80,000+ in current use. To address this gap, we mined large, publicly available toxicogenomic dataset associated with 18 known steatogenic assess responses across assays (in vitro vivo) species (i.e., rats humans). We identified genes...
The pregnane X receptor (PXR) is a ligand-activated transcription factor that acts as master regulator of metabolizing enzymes and transporters. To avoid adverse drug-drug interactions diseases such steatosis cancers associated with PXR activation, identifying drugs chemicals activate crucial importance. In this work, we developed ligand-based predictive computational models for both rat human which allowed us to identify potentially harmful evaluate species-specific effects given compound....
The current chemical space of known small molecules is estimated to exceed 1060 structures. Though the largest physical compound repositories contain only a few tens millions unique compounds, virtual screening databases this size still difficult. In recent years, application physicochemical descriptor-based profiling, such as Lipinski's rule-of-five for drug-likeness and Oprea's criteria lead-likeness, early stage filters in drug discovery has gained widespread acceptance. study, we outline...
Abstract Organ injuries caused by environmental chemical exposures or use of pharmaceutical drugs pose a serious health risk that may be difficult to assess because lack non‐invasive diagnostic tests. Mapping organ‐specific histopathology outcomes via biomarkers will provide foundation for designing precise and robust We identified co‐expressed genes (modules) specific injury endpoints using the Open Toxicogenomics Project‐Genomics Assisted Toxicity Evaluation System (TG‐GATEs) –...
Acute kidney injury (AKI) caused by drug and toxicant ingestion is a serious clinical condition associated with high mortality rates. We currently lack detailed knowledge of the underlying molecular mechanisms biological networks AKI. In this study, we carried out gene co-expression analyses using DrugMatrix—a large toxicogenomics database expression data from rats exposed to diverse chemicals—and identified modules probe molecular-level details disease. generated comprehensive set Iterative...
Animal studies are typically utilized to understand the complex mechanisms associated with toxicant-induced hepatotoxicity. Among alternative approaches animal studies, in vitro pooled human hepatocytes have potential capture population variability. Here, we examined effect of hepatotoxicant thioacetamide on hepatocytes, divided into five lots, obtained from forty diverse donors. For 24 h, were exposed vehicle, 1.33 mM (low dose), and 12 (high dose) thioacetamide, followed by RNA-seq...
The detailed structures of microsomal prostaglandin E synthase-1 (mPGES-1) binding with inhibitors have been studied, for the first time, by using a newly developed computational three-dimensional (3D) structural model mPGES-1 along 3D-quantitative structure−activity relationship (3D-QSAR) analysis. obtained satisfactory and 3D-QSAR models strongly suggest that 3D is reasonable study future design novel inhibitors.
In the future, we may be faced with need to provide treatment for an emergent biological threat against which existing vaccines and drugs have limited efficacy or availability. To prepare this eventuality, our objective was use a metabolic network-based approach rapidly identify potential drug targets prospectively screen validate novel small-molecule antimicrobials. Our target organism fully virulent Francisella tularensis subspecies Schu S4 strain, highly infectious intracellular pathogen...
Celecoxib, also known as Celebrex (approved by FDA in 1998) and remembered the fastest-selling drug history, was used a cyclooxygenase-2 (COX-2) selective inhibitor having both anti-inflammatory anticancer activities. Most recent studies have revealed that apoptotic activity of celecoxib (and its derivatives) is actually independent COX-2 inhibitory inhibits kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1), suggesting well-known not due to inhibition COX-2, but possibly PDK1. It...
In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bound the NAD+ form enzyme inhibited growth F. at concentrations near that their measured Ki. While 57 was species-specific, showed broader spectrum inhibition tularensis, Bacillus...