A5037859245- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Bioinformatics and Genomic Networks
- Enzyme Structure and Function
- Gene Regulatory Network Analysis
- Receptor Mechanisms and Signaling
- Microbial Natural Products and Biosynthesis
- Nuclear Receptors and Signaling
- Library Science and Administration
- Skin Protection and Aging
- Ubiquitin and proteasome pathways
- Metabolomics and Mass Spectrometry Studies
- Chemical Synthesis and Analysis
- Cancer, Hypoxia, and Metabolism
- Literacy, Media, and Education
- Bacterial Genetics and Biotechnology
- Library Science and Information Literacy
- Collagen: Extraction and Characterization
- Crafts, Textile, and Design
- Protease and Inhibitor Mechanisms
- Microbial Metabolic Engineering and Bioproduction
- Pharmaceutical Economics and Policy
- Glutathione Transferases and Polymorphisms
- Pharmacogenetics and Drug Metabolism
- Protein purification and stability
Boston University
2018-2025
University of Michigan
2013-2017
Beiersdorf (Germany)
2013
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...
Knowledge of protein-metabolite interactions can enhance mechanistic understanding and chemical probing biochemical processes, but the discovery endogenous ligands remains challenging. Here, we combined rapid affinity purification with precision mass spectrometry high-resolution molecular docking to precisely map physical associations 296 chemically diverse small-molecule metabolite 69 distinct essential enzymes 45 transcription factors in gram-negative bacterium Escherichia coli. We then...
Development of small molecule inhibitors protein-protein interactions (PPIs) is hampered by our poor understanding the druggability PPI target sites. Here, we describe combined application alanine-scanning mutagenesis, fragment screening, and FTMap computational hot spot mapping to evaluate energetics highly charged interface between Kelch-like ECH-associated protein 1 (KEAP1) nuclear factor erythroid 2 like (Nrf2), an important drug target. identifies four binding energy spots at active...
Starting with a crystal structure of macromolecule, computational structural modeling can help to understand the associated biological processes, and function, as well reduce number further experiments required characterize given molecular entity. In past decade, two classes powerful automated tools for investigating binding properties proteins have been developed: protein–protein docking program ClusPro FTMap FTSite programs protein hotspot identification. These methods widely used by...
An important question is how well the models submitted to CASP retain properties of target structures. We investigate several related binding. First we explore binding small molecules as probes, and count number interactions between each residue such resulting in a fingerprint. The similarity two fingerprints, one for X-ray structure other model, determined by calculating their correlation coefficient. fingerprint weakly correlates with global measures accuracy, GDT_TS higher than 80...
We study the models submitted to round 12 of Critical Assessment protein Structure Prediction (CASP) experiment assess how well binding properties are conserved when X-ray structures target proteins replaced by their models. To explore small molecule we generate distributions molecular probes – which fragment-sized organic molecules varying size, shape, and polarity around protein, count number interactions between each residue probes, resulting in a vector call fingerprint. The similarity...
Abstract The development of network inference methodologies that accurately predict connectivity in dysregulated pathways may enable the rational selection patient therapies. Accurately inferring an intracellular from data remains a very challenging problem molecular systems biology. Living cells integrate extremely robust circuits exhibit significant heterogeneity, but still respond to external stimuli predictable ways. This phenomenon allows us introduce methodology integrates measurements...
Abstract It is increasingly likely that the high incidence of off-target effects associated with targeted inhibitors due, in part, to highly complex and dysregulated intracellular molecular networks cancer. Ignoring this complexity can lead suboptimal results subsequent loss life through ineffective therapies. The phosphoinositide 3-kinase (PI3K) mitogen-activated protein kinase (MAPK) pathways are two most across all cancers. Several regulatory mechanisms have been proposed explain apparent...
Abstract Cancer cells exhibit a metabolic phenotype characterized by high rates of glucose uptake and lactate production, known as the Warburg effect. While effect normal proliferative metabolism appear similar, important molecular differences exist. We hypothesize that drivers can be modulated to impede cancer proliferation without substantial effects on tissue growth. Intracellular networks variety emergent non-linear behaviors and, result, use experimental intuition alone will not enough...
Abstract Targeted molecular inhibitors have emerged as a leading anti-cancer strategy; however, despite promising pre-clinical data, many targeted induce undesirable off-target effects in the clinic. The large number of associated with was recently termed ‘‘whack mole problem’’ because inhibiting one target often unintentionally activates another molecule. It is increasingly clear that high incidence related to complex interactions and emergent behaviors inherent highly dysregulated...