A5088974803- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- Biochemical and Structural Characterization
- Machine Learning in Materials Science
- Protein Structure and Dynamics
- Peptidase Inhibition and Analysis
- Click Chemistry and Applications
- RNA and protein synthesis mechanisms
- Supramolecular Self-Assembly in Materials
- Microbial Natural Products and Biosynthesis
- Crystallography and molecular interactions
- Advanced biosensing and bioanalysis techniques
- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Antimicrobial Resistance in Staphylococcus
- HIV-related health complications and treatments
- RNA Interference and Gene Delivery
- Innovative Microfluidic and Catalytic Techniques Innovation
- Neuropeptides and Animal Physiology
- Developmental Biology and Gene Regulation
- Enzyme Structure and Function
- Proteoglycans and glycosaminoglycans research
- Silk-based biomaterials and applications
- Aortic aneurysm repair treatments
- Neurobiology and Insect Physiology Research
Scripps Research Institute
2017-2025
Scripps Institution of Oceanography
2021-2025
Scripps (United States)
2021-2025
Lawrence Livermore National Laboratory
2020
Mayo Clinic in Arizona
2015
Mayo Clinic in Florida
2015
Glycine is a major neurotransmitter involved in several fundamental neuronal processes. The identity of the metabotropic receptor mediating slow neuromodulatory effects glycine unknown. We identified an orphan G protein–coupled receptor, GPR158, as (mGlyR). and related modulator, taurine, directly bind to Cache domain this event inhibits activity intracellular signaling complex regulator protein 7–G β5 (RGS7-Gβ5), which associated with receptor. signals through mGlyR inhibit production...
AlphaFold2 is a promising new tool for researchers to predict protein structures and generate high-quality models, with low backbone global root-mean-square deviation (RMSD) when compared experimental structures. However, it unclear if the predicted by will be valuable targets of docking. To address this question, we redocked ligands in PDBbind datasets against co-crystallized receptor using AutoDock-GPU. We find that quality measure provided during structure prediction not good predictor...
Advances in the modulation of protein-protein interactions (PPIs) enable both characterization PPI networks that govern diseases and design therapeutics probes. The shallow protein surfaces dominate PPIs are challenging to target using standard methods, approaches for accessing extended backbone structures limited. Here, we incorporate a rigid, linear, diyne brace between side chains at
Cysteine residues play key roles in protein structure and function can serve as targets for chemical probes even drugs. Chemoproteomic studies have revealed that heightened cysteine reactivity towards electrophilic probes, such iodoacetamide alkyne (IAA), is indicative of likely residue functionality. However, while the coverage chemoproteomic has increased substantially, these methods still only provide a partial assessment proteome-wide reactivity, with cysteines from low abundance...
Abstract Recent advances in structural biology have led to the publication of a wealth high‐resolution x‐ray crystallography (XRC) and cryo‐EM macromolecule structures, including many complexes with small molecules interest for drug design. While it is common incorporate information from atomic coordinates these into docking (e.g., pharmacophore models or scaffold hopping), there are limited methods directly leverage underlying density information. This desirable because does not rely on...
Staphylococcus aureus (S. aureus) is an opportunistic human pathogen that causes over one million deaths around the world each year. We recently identified a family of serine hydrolases termed fluorophosphonate binding (Fphs) play important roles in lipid metabolism and colonization host. Because many these enzymes are only expressed bacteria, they valuable targets for diagnostics therapeutics. Here, we developed screened highly diverse cyclic peptide libraries using mRNA display with...
The majority of drugs target membrane proteins, and many these proteins contain ligand binding sites embedded within the lipid bilayer. However, targeting therapeutically relevant is hindered by limited characterization both molecules that bind to them. Here, we introduce Lipid-Interacting LigAnd Complexes Database (LILAC-DB), a curated dataset 413 structures ligands bound at protein-bilayer interface. Analysis reveals lipid-exposed exhibit distinct chemical properties, such as higher...
We have developed a family of unnatural base pairs (UBPs), exemplified by the pair formed between dNaM and dTPT3, for which pairing is mediated not complementary hydrogen bonding but hydrophobic packing forces. These UBPs enabled creation first semisynthetic organisms (SSOs) that store increased genetic information use it to produce proteins containing noncanonical amino acids. However, retention was poor in some sequence contexts. Here, optimize SSO, we synthesize two novel...
Small molecules containing cyclopropane–heteroatom linkages are commonly needed in medicinal chemistry campaigns yet problematic to prepare using existing methods. To address this issue, a scalable Chan–Lam cyclopropylation reaction potassium cyclopropyl trifluoroborate has been developed. With phenol nucleophiles, the effects O-cyclopropylation, whereas with 2-pyridones, 2-hydroxybenzimidazoles, and 2-aminopyridines brings about N-cyclopropylation. The transformation is catalyzed by...
To facilitate the characterization of phase-transitioning molecules, site-specific non-perturbative infrared probes are leveraged for continuous observation self-assembly fibrils in a peptide hydrogel following stopped-flow initiation.
<h3>BACKGROUND AND PURPOSE:</h3> Rabbit aneurysm models are used for the testing of embolization devices and elucidating mechanisms human intracranial growth healing. We RNA-sequencing technology to identify genes relevant induced rabbit biology pathways potential clinical interest. This process included sequencing microRNAs, which important regulatory noncoding RNAs. <h3>MATERIALS METHODS:</h3> Elastase-induced saccular aneurysms were created at origin right common carotid artery in 6...
Macrocycles represent an important class of ligands, both in natural products and designed drugs. In drug design, macrocyclizations can impart specific ligand conformations contribute to passive permeation by encouraging intramolecular H-bonds. AutoDock-GPU Vina model macrocyclic ligands flexibly, without requiring the enumeration conformers before docking. Here, we characterize performance method for handling compounds, which is implemented default behaviour preparation with our pipeline,...
Cosolvent molecular dynamics (MD) are an increasingly popular form of simulations where small molecule cosolvents added to water-solvated protein systems. These can perform diverse target characterization tasks, including cryptic and allosteric pocket identification pharmacophore profiling, supplement suites enhanced sampling methods explore conformational landscapes. The behavior these systems is tied the used, so ability define complex mixtures critical in dictating outcome simulations....
Investigation of Lewis acid-base interactions has been conducted by ab initio calculations and Machine Learning (ML) models. This study aims to resolve two critical tasks that have not quantitatively investigated. First, ML models developed from Density Functional Theory (DFT) predict experimental BF3 affinity with Pearson correlation coefficients around 0.9 mean absolute errors 10 kJ mol-1. The are trained DFT-calculated more than 3000 adducts, input features readily obtained rdkit. Second,...
Cosolvent molecular dynamics (MDs) are an increasingly popular form of simulations where small molecule cosolvents added to water-solvated protein systems. These can perform diverse target characterization tasks, including cryptic and allosteric pocket identification pharmacophore profiling supplement suites enhanced sampling methods explore conformational landscapes. The behavior these systems is tied the used, so ability define complex mixtures critical in dictating outcome simulations....
ABSTRACT Staphylococcus aureus ( S. ) is an opportunistic human pathogen that causes over one million deaths around the world each year. We recently identified a family of serine hydrolases termed fluorophosphonate binding (Fphs) play important roles in lipid metabolism and colonization host. Because many these enzymes are only expressed bacteria, they valuable targets for diagnostics therapeutics. Here we developed screened highly diverse cyclic peptide libraries using mRNA display with...
The arylomycins are a class of natural product antibiotics that inhibit bacterial type I signal peptidase and under development as therapeutics. Four classes known, A–D. Previously, we reported the synthesis analysis representatives A, B, C showed their spectrum activity has potential to be much broader than originally assumed. Along with comparison mechanism acquired innate resistance, this led us suggest latent antibiotics, once possessed broad-spectrum activity, but which upon examination...
Partitioning of bioactive molecules, including drugs, into cell membranes may produce indiscriminate changes in membrane protein function. As a guide to safe drug development, it therefore becomes important be able predict the bilayer-perturbing potency hydrophobic/amphiphilic drugs candidates. Toward this end, we exploited gramicidin channels as molecular force probes and developed silico vitro assays measure drugs' bilayer-modifying potency. We examined eight drug-like molecules that were...
Hydrogen-bonds (H-bonds) between backbone N–H donors and CO acceptors are central to our understanding of protein structure stability. However, while interactions N atoms the following residue also common, they have been ignored as potential H-bonds due their bent geometry assumption that amide is a poor H-bond acceptor. Recently, we reported indirect experimental evidence these constitute functional H-bonds. We now report combined in molecules noncovalent interaction theoretical analysis...
The morphogenic activity of the Drosophila transcription factor bicoid (Bcd), first protein identified, is controlled by its DNA binding homeodomain. Homeodomains mediate developmental processes in all multicellular organisms, but Bcd homeodomain appears to be unique as it can bind multiple sequences and even RNA. All proteins adopt a three-helix fold, with residues third helix mediating recognition nucleic acid target via interactions major groove. Interestingly, previous studies have...
The HIV-1 capsid is an irregularly shaped complex of about 1200 protein chains containing the viral genome and several proteins. Together, these components are key to unlocking passage into nucleus, allowing for permanent integration host cell genome. Recent interest role in replication has been driven by approval first-in-class drug lenacapavir, which marks first approved target a non-enzymatic protein. In addition other small molecules such as drug-like compound PF74, anionic sugar...
Abstract Investigation of Lewis acid–base interactions has been conducted by ab initio calculations and machine learning (ML) models. This study aims to resolve two critical tasks that have not quantitatively investigated. First, ML models developed from density functional theory (DFT) predict experimental BF 3 affinity with Pearson correlation coefficients around 0.9 mean absolute errors 10 kJ mol −1 . The are trained DFT‐calculated more than 3000 adducts, input features readily obtained...
Recent advances in structural biology have led to the publica- tion of a wealth high resolution x-ray crystallography and cryo-EM macromolecule structures, including many complexes with small molecules interest for drug design. While it is com- mon incorporate information from atomic coordinates these into docking (e.g. pharmacophore models or scaffold hopping), there are limited methods directly leverage underlying density information. This desirable because does not rely on determination...