A5044356220- Biochemical Acid Research Studies
- Metabolism and Genetic Disorders
- Drug Transport and Resistance Mechanisms
- Alcoholism and Thiamine Deficiency
- Pharmacological Effects and Toxicity Studies
- Drug Solubulity and Delivery Systems
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Parasitic Diseases Research and Treatment
- Pharmacogenetics and Drug Metabolism
- Biochemical and Molecular Research
- Formal Methods in Verification
- Insect symbiosis and bacterial influences
- Amino Acid Enzymes and Metabolism
- HIV/AIDS drug development and treatment
- Pharmacological Receptor Mechanisms and Effects
- Tuberculosis Research and Epidemiology
- Insects and Parasite Interactions
- SARS-CoV-2 and COVID-19 Research
- Chronic Myeloid Leukemia Treatments
- Machine Learning and Algorithms
- Pain Mechanisms and Treatments
- Computational Drug Discovery Methods
- Eosinophilic Disorders and Syndromes
- Acute Myeloid Leukemia Research
Post Graduate Institute of Medical Education and Research
2021-2025
Enanta Pharmaceuticals (United States)
2022-2024
University of Illinois Chicago, Rockford campus
2007-2024
Illinois College
2007-2024
University of Southern California
2023
University of Illinois Chicago
2023
Center for Drug Evaluation and Research
2023
United States Food and Drug Administration
2023
Bristol-Myers Squibb (United States)
2015-2022
Rutgers, The State University of New Jersey
2009-2020
Because modulation of P-glycoprotein (Pgp) through inhibition or induction can lead to drug-drug interactions by altering intestinal, central nervous system, renal, biliary efflux, it is anticipated that information regarding the potential interaction drug candidates with Pgp will be a future regulatory expectation. Therefore, able utilize in vitro findings guide clinical studies, utility five probe substrates (calcein-AM, colchicine, digoxin, prazosin, and vinblastine) was evaluated...
Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer's disease (AD) pathology. We sought to understand whether mGluR5's role AD requires signaling. used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) separate its well-known physiological signaling from pathological mediating amyloid-β oligomer (Aβo) action. Binding of the SAM does not change but strongly reduces interaction with cellular prion protein (PrPC) bound Aβo. The compound prevents Aβo-induced...
Enzymes of central carbon metabolism (CCM) in Mycobacterium tuberculosis (Mtb) make an important contribution to the pathogen's virulence. Evidence is emerging that some these enzymes are not simply playing metabolic roles for which they annotated, but can protect pathogen via additional functions. Here, we found deficiency 2-hydroxy-3-oxoadipate synthase (HOAS), E1 component α-ketoglutarate (α-KG) dehydrogenase complex (KDHC), did lead general perturbation or growth impairment Mtb, only...
Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been and show efficacy in various rodent pain models. (S)-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) (34) was highly selective, CNS penetrant, potent inhibitor from novel class bi(hetero)aryl ethers. BMS-986176/LX9211 showed excellent two models central...
The COVID-19 pandemic has led to the deaths of millions people and severe global economic impacts. Small molecule therapeutics have played an important role in fight against SARS-CoV-2, virus responsible for COVID-19, but their efficacy been limited scope availability, with many unable access benefits, better options are needed. EDP-235 is specifically designed inhibit SARS-CoV-2 3CLpro, potent nanomolar activity all variants date, as well clinically relevant human zoonotic coronaviruses....
Spectroscopic identification and characterization of covalent noncovalent intermediates on large enzyme complexes is an exciting challenging area modern enzymology. The Escherichia coli pyruvate dehydrogenase multienzyme complex (PDHc), consisting multiple copies enzymic components coenzymes, performs the oxidative decarboxylation to acetyl-CoA central carbon metabolism linking glycolysis Krebs cycle. On basis earlier studies, we hypothesized that dynamic regions E1p component, which undergo...
Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe discovery optimization a novel oxazolidinone-based chemotype identify BMS-955829 (4), compound with high functional PAM potency, excellent mGluR5 binding affinity, low fold shift, selectivity for subtype. The shift absence agonist activity proved critical identification...
Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 (4), highly selective, CNS-penetrable, and potent AAK1 inhibitor, has advanced into phase II human trials. On exploring the structure-activity relationship (SAR) around this biaryl alkyl ether chemotype, several additional compounds were found to be selective inhibitors with good druglike properties. Among these, 43 58 showed very efficacy...
Knowledge of the state ionization and tautomerization heteroaromatic cofactors when enzyme-bound is essential for formulating a detailed stepwise mechanism via proton transfers, most commonly observed contribution to enzyme catalysis. In bifunctional coenzyme, thiamin diphosphate (ThDP), both aromatic rings participate in catalysis, thiazolium ring as an electrophilic covalent catalyst 4'-aminopyrimidine acid-base involving its 1',4'-iminopyrimidine tautomeric form. Two four states ThDP are...
Thiamin diphosphate (ThDP) dependent enzymes perform crucial C-C bond forming and breaking reactions in sugar amino acid metabolism biosynthetic pathways via a sequence of ThDP-bound covalent intermediates. A member this superfamily, yeast pyruvate decarboxylase (YPDC) carries out the nonoxidative decarboxylation is mechanistically simpler ThDP enzyme. YPDC variants created by substitution at active center (D28A, E51X, E477Q) on substrate activation pathway (E91D C221E) display varying...
The objective was to investigate the interplay between transporter expression levels and substrate affinity in controlling influence of aqueous boundary layer (ABL) resistance on kinetics an over-expression system. Taurocholate flux measured across human apical sodium-dependent bile acid (hASBT)-Madin-Darby canine kidney monolayers different occasions kinetic parameters estimated with without considering ABL. In error-free simulation/regression studies, values were generated a range...
The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling association with N-methyl-d-aspartate (NMDAR). We describe synthesis 1H-pyrazolo[3,4-b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs) without inherent agonist activity. A facile convergent synthetic route provided access a structurally diverse set analogues that contain neither aryl-acetylene-aryl nor...
Thiamin diphosphate (ThDP) is a key coenzyme in sugar metabolism. The 4′-aminopyrimidine ring of ThDP cycles through several ionization and tautomeric states during enzyme catalysis, but it not fully understood which are adopted the individual steps catalytic cycle. has been synthesized with labels selectively inserted into C2 C6′ positions, as well amino group, creating [C2, C6′-13C2] thiamin [N4′-15N] thiamin. Magic-angle spinning (MAS) NMR spectroscopy employed to record 13C 15N chemical...
The first component (E1o) of the Escherichia coli 2-oxoglutarate dehydrogenase complex (OGDHc) was engineered to accept substrates lacking 5-carboxylate group by subjecting H260 and H298 saturation mutagenesis. Apparently, is required for substrate recognition, but could be replaced with hydrophobic residues similar molecular volume. To interrogate whether second would allow synthesis acyl-coenzyme A derivatives, hybrid complexes consisting recombinant components OGDHc (o) pyruvate (p)...