Recent Publications

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Bioorg. Med. Chem. Lett. 2024
Arylalkylamine N-acetyltransferase (AANAT) catalyzes the  rate-limiting step in melatonin synthesis and is a potential target for  disorders involving melatonin overproduction, such as seasonal affective  disorder. Previously described AANAT inhibitor bromoacetyltryptamine  (BAT) and benzothiophenes analogs were reported to react with CoASH to  form potent bisubstrate inhibitors through AANAT’s alkyltransferase  function, which is secondary to its role as an acetyltransferase. We  replaced the bromoacetyl group in BAT with various Michael acceptors to  mitigate possible off-target activity of its bromoacetyl group.  Additionally, we modified the length of the carbon linker between the  Michael acceptor and indole bicycle of tryptamine to determine its  effect on potency. An AANAT enzymatic assay showed a two-carbon linker  present in BAT was optimal, while none of the new warheads had activity.  Kinetic analysis indicated that these Michael acceptors reacted with  CoASH much slower than BAT and not within the timeframe of our enzymatic  assay. Additionally, we confirmed earlier reports that the  acetyltransferase function of AANAT follows an ordered bi bi mechanism  in which AcCoA binds before serotonin. In contrast, BAT’s  alkyltransferase kinetics revealed a bi uni mechanism in which BAT binds  to AANAT before CoASH. Our model combines both functions of AANAT into  one kinetic mechanism. 

ChemMedChem, 2023
Circadian rhythm (CR) dysregulation negatively impacts health and  contributes to mental disorders. The role of melatonin, a hormone  intricately linked to CR, is still a subject of active study. The enzyme  arylalkylamine N-acetyltransferase (AANAT) is responsible for melatonin  synthesis, and it is a potential target for disorders that involve  abnormally high melatonin levels, such as seasonal affective disorder  (SAD). Current AANAT inhibitors suffer from poor cell permeability,  selectivity, and/or potency. To address the latter, we have employed an  X-ray crystal-based model to guide the modification of a previously  described AANAT inhibitor, containing a rhodanine-indolinone core. We  made various structural modifications to the core structure, including  testing the importance of a carboxylic acid group thought to bind in the  CoA site, and we evaluated these changes using MD simulations in  conjunction with enzymatic assay data. Additionally, we tested three  AANAT inhibitors in a zebrafish locomotion model to determine their  effects in vivo. Key discoveries were that potency could be modestly  improved by replacing a 5-carbon alkyl chain with rings and that the  central rhodanine ring could be replaced by other heterocycles and  maintain potency. 

Biophysical Journal, 2022
The human L-type amino acid transporter 1 (LAT1; SLC7A5) is a membrane transporter of amino acids, thyroid hormones, and drugs such as the Parkinson’s disease drug levodopa (L-Dopa). LAT1 is found in the blood-brain barrier, testis, bone marrow, and placenta, and its dysregulation has been associated with various neurological diseases, such as autism and epilepsy, as well as cancer. In this study, we combine metainference molecular dynamics simulations, molecular docking, and experimental testing, to characterize LAT1-inhibitor interactions. We first conducted a series of molecular docking experiments to identify the most relevant interactions between LAT1’s substrate-binding site and ligands, including both inhibitors and substrates. We then performed metainference molecular dynamics simulations using cryoelectron microscopy structures in different conformations of LAT1 with the electron density map as a spatial restraint, to explore the inherent heterogeneity in the structures. We analyzed the LAT1 substrate-binding site to map important LAT1-ligand interactions as well as newly described druggable pockets. Finally, this analysis guided the discovery of previously unknown LAT1 ligands using virtual screening and cellular uptake experiments. Our results improve our understanding  of LAT1-inhibitor recognition, providing a framework for rational design of future lead compounds targeting this key drug target.  

Nucleosides, Nucleotides & Nucleic Acids, 2022
We report the synthesis and cytotoxicity in MCF-7 and MDA-MB-231 breast  cancer cells of novel 1,2,3- and 1,2,4-triazolyl analogs of ribavirin.  We modified ribavirin’s carboxamide moiety to test the effects of  lipophilic groups. 1-β-D-Ribofuranosyl-1H-1,2,3-triazoles were  prepared using Click Chemistry, whereas an unprecedented application of a  prior 1,2,4-triazole ring synthesis was used for 1-β-D-ribofuranosyl-1H-1,2,4-triazole  analogs. Though cytotoxicity was mediocre and there was no correlation  with lipophilicity, we discovered that a structurally similar  concentrative nucleoside transporter 2 (CNT2) inhibitor was modestly  cytotoxic (MCF-7 IC50 of 42 µM). These syntheses could be used to efficiently investigate variation in the nucleobase. 

ChemMedChem, 2021

 The L‐type amino acid transporter 1 (LAT1, SLC7A5) imports dietary amino  acids and amino acid drugs (e.g.  L‐DOPA) into the brain, and it plays a  role in cancer metabolism. Though there have been numerous reports of  LAT1‐targeted amino acid‐drug conjugates (prodrugs), identifying the  structural determinants to enhance substrate activity has been  challenging. In this work, we investigated the position and orientation  of a carbonyl group in linking hydrophobic moieties including the  anti‐inflammatory drug ketoprofen to L‐tyrosine and L‐phenylalanine. We  found that esters of  meta‐carboxyl L‐phenylalanine had better LAT1  transport rates than the corresponding acylated L‐tyrosine analogs.  However, as the size of the hydrophobic moiety increased, we observed a  decrease in LAT1 transport rate with a concomitant increase in potency  of inhibition. Our results have important implications for designing  amino acid prodrugs that target LAT1 at the blood‐brain barrier (BBB) or  on cancer cells. 

https://orcid.org/0000-0001-8313-0879