A5102826918- Computational Drug Discovery Methods
- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Metabolomics and Mass Spectrometry Studies
- Analytical Chemistry and Chromatography
- Histone Deacetylase Inhibitors Research
- Cancer, Hypoxia, and Metabolism
- Liver Disease Diagnosis and Treatment
- Immune Response and Inflammation
- Cancer therapeutics and mechanisms
- Protein Degradation and Inhibitors
- Statistical Methods in Clinical Trials
- Gastroesophageal reflux and treatments
- Protein Structure and Dynamics
- Antibiotics Pharmacokinetics and Efficacy
- Lung Cancer Research Studies
- Medical Malpractice and Liability Issues
- Advanced Drug Delivery Systems
- Nitric Oxide and Endothelin Effects
- HIV/AIDS drug development and treatment
- Drug-Induced Hepatotoxicity and Protection
- Peroxisome Proliferator-Activated Receptors
- Clinical Reasoning and Diagnostic Skills
- Acute Myeloid Leukemia Research
- Pancreatic and Hepatic Oncology Research
National Center for Advancing Translational Sciences
2016-2025
Uka Tarsadia University
2017-2024
Madan Bhandari Academy of Health Sciences
2024
National Institutes of Health
2015-2023
Jersey Shore University Medical Center
2023
St. George's University
2023
Center for Discovery
2023
Hospital of the University of Pennsylvania
2023
Tata Consultancy Services (India)
2022
Pfizer (United States)
2016-2021
Diagnostic errors contribute to patient harm, though few data exist describe their prevalence or underlying causes among medical inpatients.
A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via optimized linker. Several these were highly potent (IC50 < 10 nM) selective against PI3Kγ, δ HDAC6 enzymes exhibited good antiproliferative activity multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant FLT3-resistant AML lines primary blasts from patients,...
Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) possess vital physiological toxicological functions in areas such as CNS, inflammation, metabolic disorders, cancers. Overexpression certain ALDHs (e.g., ALDH1A1) is an important biomarker cancers cancer stem cells (CSCs) indicating potential need identification development small molecule ALDH inhibitors. Herein, a newly designed series quinoline-based analogs ALDH1A1 inhibitors...
Abstract Isocitrate dehydrogenase 1 and 2 (IDH1 IDH2) are key metabolic enzymes that mutated in a variety of cancers to confer gain-of-function activity resulting the accumulation an oncometabolite, D-2-hydroxyglutarate (2-HG). Accumulation 2-HG can result epigenetic dysregulation block cellular differentiation, suggesting these mutations play role neoplasia. Based on its potential as cancer target, number small molecule inhibitors have been developed specifically inhibit mutant forms IDH...
Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation reduced nicotinamide adenine dinucleotide as final step in glycolytic pathway. Glycolysis plays an important role metabolic plasticity cancer cells and has long been recognized a potential therapeutic target. Thus, potent, selective inhibitors LDH represent attractive approach. However, date, pharmacological agents have failed achieve significant target engagement vivo, possibly because...
NADPH oxidases (NOX's), and the reactive oxygen species (ROS) they produce, play an important role in host defense, thyroid hormone synthesis, apoptosis, gene regulation, angiogenesis other processes. However, overproduction of ROS by these enzymes is associated with cardiovascular disease, fibrosis, traumatic brain injury (TBI) diseases. Structural similarities between NOX's have complicated development specific inhibitors. Here, we report NCATS-SM7270, a small molecule optimized from...
Advancement of in silico tools would be enabled by the availability data for metabolic reaction rates and intrinsic clearance (CL<sub>int</sub>) a diverse compound structure set specific enzymes. Our goal is to measure CL<sub>int</sub> large compounds with each major human cytochrome P450 (P450) isozyme. To achieve our goal, it utmost importance develop an automated, robust, sensitive, high-throughput stability assay that can efficiently handle volume sets. The substrate depletion method [in...
Hepatic metabolic stability is a key pharmacokinetic parameter in drug discovery. Metabolic usually assessed microsomal fractions and only the best compounds progress discovery process. A high-throughput single time point substrate depletion assay rat liver microsomes (RLM) employed at National Center for Advancing Translational Sciences. Between 2012 2020, RLM data was generated ~ 24,000 from more than 250 projects that cover wide range of pharmacological targets cellular pathways. Although...
Preclinical pharmacokinetics (PK) and In Vitro ADME properties of GS-441524, a potential oral agent for the treatment Covid-19, were studied. GS-441524 was stable in vitro liver microsomes, cytosols, hepatocytes mice, rats, monkeys, dogs, humans. The plasma free fractions 62-78% across all studied species. transporter study results showed that substrate MDR1, BCRP, CNT3, ENT1, ENT2; but not CNT1, CNT2, ENT4. had low to moderate clearance (CLp), ranging from 4.1 mL/min/kg dogs 26 mice; steady...
Efficiently circumventing the blood-brain barrier (BBB) poses a major hurdle in development of drugs that target central nervous system. Although there are several methods to determine BBB permeability small molecules, Parallel Artificial Membrane Permeability Assay (PAMPA) is one most common assays drug discovery due its robust and high-throughput nature. Drug long costly venture, thus, any advances streamline this process beneficial. In study, ∼2,000 compounds from over 60 NCATS projects...
Abstract Over the last few decades, chemists have become skilled at designing compounds that avoid cytochrome P (CYP) 450 mediated metabolism. Typical screening assays are performed in liver microsomal fractions and it is possible to overlook contribution of cytosolic enzymes until much later drug discovery process. Few data exist on enzyme-mediated metabolism no reliable tools available help design away from such liabilities. In this study, we screened 1450 for cytosol-mediated metabolic...
Problems with drug ADME are responsible for many clinical failures. By understanding the properties of marketed drugs and modeling how chemical structure contributes to these inherent properties, we can help new projects reduce their risk profiles. Kinetic aqueous solubility, parallel artificial membrane permeability assay (PAMPA), rat liver microsomal stability constitute Tier I assays at National Center Advancing Translational Sciences (NCATS). Using recent data generated from in-house...
Cytochrome P450 enzymes are responsible for the metabolism of >75% marketed drugs, making it essential to identify contributions individual cytochromes total clearance a new candidate drug. Overreliance on one cytochrome levies high risk drug-drug interactions; and considering that several human polymorphic, can also lead highly variable pharmacokinetics in clinic. Thus, would be advantageous understand likelihood chemical entities interact with major at an early stage drug discovery...
Currently, approximately 80,000 chemicals are used in commerce. Most have little-to-no toxicity information. The U.S. Toxicology the 21st Century (Tox21) program has conducted a battery of vitro assays using quantitative high-throughput screening (qHTS) platform to gain information on environmental chemicals. Due technical challenges, standard methods for providing xenobiotic metabolism could not be applied qHTS assays. To address this limitation, we screened Tox21 10,000-compound (10K)...
Abstract Natural Products (NPs) are increasingly utilized worldwide for their potential therapeutic benefits, including central nervous system (CNS) disorders. Studies have shown açai berries mitigating Parkinson’s disease progression through dopaminergic neuroprotection via Nrf-2 HO-1 pathways. Ashwagandha, an evergreen shrub, has as a neurodegenerative disorders axonal regeneration in Aβ25-35-treated cortical neurons vitro. In most cases, promising NPs tested using vitro assays or simpler...
We report the optimization of a series IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced key compound 27 that displays potent and selective inhibition IRAK1, IRAK4, FLT3, reduced block hERG, good pharmacokinetic properties. In mouse xenograft model acute myeloid leukemia (AML), produces survival prolongation superior to gilteritinib, leading FDA-approved FLT3 inhibitor currently used treat AML.
Impairment of drug disposition in the liver during inflammation has been attributed to downregulation gene expression drug-metabolizing enzymes (DMEs) and transporters. Inflammatory responses are primarily mediated by Toll-like receptors (TLRs). We have recently shown that activation TLR2 or TLR4 lipoteichoic acid (LTA) lipopolysaccharide (LPS), respectively, leads DMEs/transporters. However, molecular mechanism underlying this is not fully understood. The xenobiotic nuclear receptors,...
The active sites of hundreds human α-ketoglutarate (αKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design selective inhibitors. We identified a noncatalytic cysteine (Cys481 in KDM5A) near KDM5 histone H3 lysine 4 demethylases, is absent other demethylase families, that could be explored for interaction with cysteine-reactive electrophile acrylamide. synthesized analogs thienopyridine-based inhibitor chemotype, namely,...
The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration-response curves, which was designed identify active against liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across range 5 11 concentrations, for...
Inappropriate use of prescription drugs is potentially more harmful in fetuses/neonates than adults. Cytochrome P450 (CYP) 3A subfamily undergoes developmental changes expression, such as a transition from CYP3A7 to CYP3A4 shortly after birth, which provides potential way distinguish medication effects on and The purpose this study was build first-in-class predictive models for both inhibitors substrates CYP3A7/CYP3A4 using chemical structure analysis. Three metrics were used evaluate model...