A5002266692- Click Chemistry and Applications
- Growth Hormone and Insulin-like Growth Factors
- Chemical Synthesis and Analysis
- Synthesis and Catalytic Reactions
- RNA and protein synthesis mechanisms
- PI3K/AKT/mTOR signaling in cancer
- Nuclear Structure and Function
- Coordination Chemistry and Organometallics
- Metabolism, Diabetes, and Cancer
- Cancer-related Molecular Pathways
- Synthesis and Reactivity of Heterocycles
- Protein Structure and Dynamics
- RNA modifications and cancer
- Galectins and Cancer Biology
- Protein Tyrosine Phosphatases
- Monoclonal and Polyclonal Antibodies Research
- RNA Research and Splicing
- Bioactive Compounds and Antitumor Agents
- Protein Degradation and Inhibitors
- Mosquito-borne diseases and control
- Pharmacological Receptor Mechanisms and Effects
- Catalytic Cross-Coupling Reactions
- Bacteriophages and microbial interactions
- Advanced Breast Cancer Therapies
- Synthesis and Characterization of Heterocyclic Compounds
George Mason University
2022-2024
Jupiter (United States)
2017
Stony Brook University
2015
Stony Brook Medicine
2015
Queen's University
2009-2010
Computational Physics (United States)
2005
Pearl River Community College
2004
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways thus an attractive therapeutic target for diabetes obesity. Starting with high micromolar lead compound, structure-based optimization novel PTP1B inhibitors by extension molecule from enzyme active site into second phosphotyrosine binding described. Medicinal chemistry, guided X-ray complex structure molecular modeling, has yielded low nanomolar in efficient manner. Compounds this...
The SET and MYND Domain (SMYD) proteins comprise a unique family of multi-domain histone methyltransferases that are implicated in human cancer progression. Here we report an analysis the crystal structure full length SMYD3 complex with analog S-adenosyl methionine (SAM) methyl donor cofactor. revealed overall compact architecture which “split-SET” domain adopts canonical fold closely assembles Zn-binding C-terminal superhelical 9 α-helical bundle similar to observed for mouse SMYD1...
// Mark A. Brown 1, * , Kenneth Foreman 2, June Harriss 3 Chhaya Das Li Zhu Melissa Edwards Salam Shaaban 4 Haley Tucker 1 Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA 2 Coferon Inc., Stony Brook, NY 11791, University Texas at Austin, Institute Cellular and Molecular Biology, TX 78712, Abbvie, Worcester, MA 01605, These authors have contributed equally to this work Correspondence to: Tucker, e-mail: haleytucker@austin.utexas.edu Keywords: HSP90,...
We have developed and tested an absolute free energy perturbation (FEP) protocol, which combines all-atom molecular dynamics, replica exchange with solute tempering (REST) enhanced sampling, a spherical harmonic restraint applied to ligand. Our objective was compute the binding together underlying mechanism for ligand, binds diffusively protein. Such ligands represent nearly impossible targets traditional FEP simulations. To test our FEP/REST we selected conserved motif peptide KKPK termed...
β-Tryptase, a homotetrameric serine protease, has four identical active sites facing central pore, presenting an optimized setting for the rational design of bivalent inhibitors that bridge two adjacent sites. Using diol, hydroxymethyl phenols or benzoyl methyl hydroxamates, and boronic acid chemistries to reversibly join [3-(1-acylpiperidin-4-yl)phenyl]methanamine core ligands, we have successfully produced series self-assembling heterodimeric inhibitors. These tryptase demonstrate superior...
Venezuelan equine encephalitis virus (VEEV) is a highly virulent pathogen whose nuclear localization signal (NLS) sequence from capsid protein binds to the host importin-α transport and blocks import. We studied molecular mechanisms by which two small ligands, termed I1 I2, interfere with binding of VEEV's NLS peptide protein. To this end, we performed all-atom replica exchange dynamics simulations probing competitive VEEV coreNLS or I2 ligand major site. As reference, used our previous...
This letter describes a series of small molecule inhibitors IGF-1R with unique time-dependent binding kinetics and slow off-rates. Structure-activity structure-kinetic relationships were elucidated guided further optimizations within the series, culminating in compound 2. With an dissociative half-life (t 1/2) >100 h, 2 demonstrated significant extended PD effects conjunction tumor growth inhibition xenograft models at remarkably low intermittent dose, which correlated observed vitro...
We describe the successful application of a novel approach for generating dimeric Myc inhibitors by modifying and reversibly linking two previously described small molecules. synthesized directed libraries monomers, each comprised ligand, connector, bioorthogonal linker element, to identify optimal dimer configuration required inhibit Myc. identified combinations termed self-assembling inhibitors, which displayed synergistic inhibition Myc-dependent cell growth. confirmed that these directly...
Free energy perturbation coupled with replica exchange solute tempering (FEP/REST) offers a rigorous approach to compute relative free changes for ligands. To determine the applicability of FEP/REST ligands distributed binding poses, we considered two alchemical transformations involving three putative inhibitors I0, I1, and I2 Venezuelan equine encephalitis virus nuclear localization signal sequence importin-α (impα) transporter protein. I0 → I1 transformations, respectively, increase or...
Although Venezuelan equine encephalitis virus (VEEV) is a life-threatening pathogen with capacity for epidemic outbreaks, there are no FDA-approved VEEV antivirals humans. cytotoxicity partially attributed to the formation of tetrameric complex between capsid protein, nuclear import proteins importin-α and importin-β, export protein CRM1, which together block trafficking through pore complex. Experimental studies have identified small molecules from CL6662 scaffold as potential inhibitors...
Imidazo[1,5-a]pyrazines 1 undergo regioselective C3-metalation and C5/C3-dimetalation to afford a range of functionalized derivatives 2a−2g (Table 1), 4a−4d 2). Under similar conditions, the C3-methyl 2a 5 surprising C5-deprotonation afford, after electrophile quench, products 4b 6a−6p 3), results that are rationalized by quantum mechanical calculations. Benzamide 7b, obtained from such metalation chemistry followed Suzuki cross coupling, undergoes directed remote metalation-cyclization 8,...
This report describes the investigation of a series 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors insulin-like growth factor-1 receptor (IGF-1R) and insulin (IR). Structure-activity relationship exploration optimization leading to identification, characterization, pharmacological activity compound 9b, potent, selective, well-tolerated, orally bioavailable dual inhibitor IGF-1R IR with in vivo efficacy tumor xenograft models, is discussed.
The aminopeptidase activity (AP) of the leukotriene A4 hydrolase (LTA4H) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on benefits augmenting LTA4H AP and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP). However, recent have introduced substantial complexity disconnecting modulator 4-methoxydiphenylmethane (4MDM) from PGP follows: (1) 4MDM inhibits hydrolysis subsequently inhibition activity, (2) activates same in presence...
Empirical data has shown that bivalent inhibitors can bind a given target protein significantly better than their monomeric counterparts. However, predicting the corresponding theoretical fold improvements been challenging. The current work builds off reacted-site probability approach to provide straightforward baseline reference model for fold-improvements in effective affinity of dimerized ligands over For more familiar irreversibly linked bivalents, predicts weak dependence on tether...
Tryptase, a serine protease released from mast cells, is implicated in many allergic and inflammatory disorders. Human tryptase donut-shaped tetramer with the active sites facing inward forming central pore. Bivalent ligands spanning two potently inhibit this configuration, but these large compounds have poor drug-like properties. To overcome some of challenges, we developed self-assembling molecules, called coferons, which deliver larger compound parts. Using pharmacophoric core reversibly...
Several small molecule inhibitors have been designed to block binding of the Venezuelan equine encephalitis virus (VEEV) nuclear localization signal (NLS) sequence importin-α transport protein. To probe inhibition mechanism on a molecular level, we used all-atom explicit water replica exchange dynamics study two inhibitors, I1 and I2, coreNLS peptide, representing core fragment VEEV NLS sequence. Our objective was evaluate possibility masking wherein these occurs prior its importin-α. We...