A5081618576- Computational Drug Discovery Methods
- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Cell Adhesion Molecules Research
- Click Chemistry and Applications
- Cytokine Signaling Pathways and Interactions
- Chemical Synthesis and Analysis
- Immune Response and Inflammation
- T-cell and B-cell Immunology
- NF-κB Signaling Pathways
- Enzyme Structure and Function
- Receptor Mechanisms and Signaling
- Genomics, phytochemicals, and oxidative stress
- Protein Degradation and Inhibitors
- interferon and immune responses
- HER2/EGFR in Cancer Research
- Immune Cell Function and Interaction
- Signaling Pathways in Disease
- Estrogen and related hormone effects
- Advanced Biosensing Techniques and Applications
- Protein Kinase Regulation and GTPase Signaling
- Ubiquitin and proteasome pathways
- Nerve injury and regeneration
- Neuroblastoma Research and Treatments
- Melanoma and MAPK Pathways
Boston University
2015-2025
Biogen (United States)
1997-2007
University of Lausanne
2006
Cleveland Clinic
2005
Icahn School of Medicine at Mount Sinai
2005
University of California, San Francisco
2005
Sunesis (United States)
2005
Massachusetts Institute of Technology
2005
NsGene (Denmark)
2005
Stony Brook University
2003
We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations 22 4.6 micromolar, respectively. Formation an intermediate complex between the intact trimer results 600-fold accelerated dissociation rate leads to dissociation. A structure solved by x-ray crystallography reveals...
Despite the growing number of examples small-molecule inhibitors that disrupt protein–protein interactions (PPIs), origin druggability such targets is poorly understood. To identify druggable sites in interfaces we combine computational solvent mapping, which explores protein surface using a variety small “probe” molecules, with conformer generator to account for side-chain flexibility. Applications unliganded structures 15 PPI target proteins show comprise cluster binding hot spots,...
Isoniazid (INH), a frontline antitubercular drug, inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis , by forming covalent adduct with NAD cofactor. Here, we report that INH-NAD is slow, tight-binding competitive inhibitor of InhA. Demonstration binds to WT InhA two-step enzyme inhibition mechanism, initial, weak binding ( K –1 = 16 ± 11 nM) followed slow conversion final inhibited complex (EI*) overall i 0.75 0.08 nM, reconciles existing contradictory values for inhibitory...
Glial cell line-derived neurotrophic factor (GDNF)-dependent activation of the tyrosine kinase receptor RET is necessary for kidney and enteric neuron development, mutations in are associated with human diseases. Activation by GDNF has been shown to require an accessory component, GDNFR-α (RETL1). We report isolation characterization rat cDNAs a novel cell-surface protein, RETL2, that shares 49% identity RETL1. Both RETL1 RETL2 can mediate dependent phosphorylation RET, but they exhibit...
TGF-β family ligands are translated as prepropeptide precursors and processed into mature C-terminal dimers that signal by assembling a serine/threonine kinase receptor complex containing type I II components. Many secreted in latent form cannot bind their receptor, due to the pro-region remaining associated with ligand noncovalent after proteolytic cleavage. Here we show anti-Müllerian hormone (AMH), involved reproductive development, must be cleaved its (AMHRII), but dissociation of from...
Profiling the reactivity and stability of S<sup>VI</sup>–F warheads towards nucleophilic amino acids for development biochemical probe compounds.
Molecular dynamics (MD) simulations of proteins reveal the existence many transient surface pockets; however, factors determining what small subset these represent druggable or functionally relevant ligand binding sites, called "cryptic sites," are not understood. Here, we examine multiple X-ray structures for a set with validated cryptic using computational hot spot identification tool FTMap. The results show that sites in ligand-free generally have strong energy very close by. As expected,...
In the context of protein-protein interactions, term "hot spot" refers to a residue or cluster residues that makes major contribution binding free energy, as determined by alanine scanning mutagenesis. contrast, in pharmaceutical research, hot spot is site on target protein has high propensity for ligand and hence potentially important drug discovery. Here we examine relationship between these two concepts comparing data set 15 proteins with results from mapping surfaces sites can bind...
A powerful early approach to evaluating the druggability of proteins involved determining hit rate in NMR-based screening a library small compounds. Here, we show that computational analog this method, based on mapping using molecules as probes, can reliably reproduce results from and provide more meaningful assessment cases where two approaches disagree. We apply method large set proteins. The that, because is biophysics binding rather than empirical parametrization, information be gained...
Beyond rule-of-five (bRo5) compounds are increasingly used in drug discovery. Here we analyze 37 target proteins that have bRo5 drugs or clinical candidates. Targets can benefit from if they "complex" hot spot structure with four more hots spots, including some strong ones. Complex I targets show positive correlation between binding affinity and molecular weight. These conventionally druggable, but reaching additional spots enables improved pharmaceutical properties. II targets, mostly...
The design of PROteolysis-TArgeting Chimeras (PROTACs) requires bringing an E3 ligase into proximity with a target protein to modulate the concentration latter through its ubiquitination and degradation. Here, we present method for generating high-accuracy structural models ligase–PROTAC–target ternary complexes. is dependent on two computational innovations: adding "silent" convolution term efficient protein–protein docking program eliminate poses that do not have acceptable linker...
Post-translational modifications of the developmental signaling protein Sonic hedgehog (Shh) by a long-chain fatty acid at N-terminus and cholesterol C-terminus greatly activate in cell-based assay. To investigate structural determinants this activation phenomenon, hydrophobic hydrophilic moieties have been introduced chemical mutagenic methods to soluble N-terminal domain Shh tested both vitro vivo assays. A wide variety increased potency when added protein, ranging from acids amino acids,...
BAFF (B cell activating factor of the TNF family, also known as BlyS and TALL-1), a family cytokine critical for development function B cells, has been reported to bind three receptors, BCMA maturation protein), TACI (transmembrane activator CAML [calcium-modulator cyclophilin ligand] interactor), BAFFR (BAFF receptor), but with widely conflicting values affinity selectivity binding. additionally APRIL (a proliferation-inducing ligand), ligand most homologous BAFF. Using soluble, monomeric...
PEGylation of IFN-α has been used successfully to improve the pharmacokinetic properties and efficacy drug. To prepare a PEGylated form human interferon-β-1a (IFN-β-1a) suitable for testing in vivo, we have synthesized 20 kDa mPEG-O-2-methylpropionaldehyde it modify N-terminal α-amino group cytokine. The protein retained ∼50% activity unmodified had significantly improved following intravenous administration rats. clearance volume distribution at steady state were reduced ∼30-fold ∼4-fold,...