A5009751380- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Histone Deacetylase Inhibitors Research
- Force Microscopy Techniques and Applications
- Endoplasmic Reticulum Stress and Disease
- biodegradable polymer synthesis and properties
- Crystallography and molecular interactions
- vaccines and immunoinformatics approaches
- Machine Learning in Materials Science
- Lipid Membrane Structure and Behavior
- Mechanical and Optical Resonators
- Fuzzy Logic and Control Systems
- Nanomaterials for catalytic reactions
- Parkinson's Disease Mechanisms and Treatments
- Electron and X-Ray Spectroscopy Techniques
- Advanced NMR Techniques and Applications
- Molecular Junctions and Nanostructures
- Ubiquitin and proteasome pathways
- Biotin and Related Studies
- Cell death mechanisms and regulation
- Advanced Chemical Physics Studies
- Autophagy in Disease and Therapy
- Enzyme Structure and Function
- Multi-Criteria Decision Making
Biogen (United States)
2019-2024
Michigan State University
2016-2018
QuantumBio (United States)
2018
National Chemical Laboratory
2014
Pharmacological activation of the E3 ligase Parkin represents a rational therapeutic intervention for treatment Parkinson's disease. Here we identify several compounds that enhance activity wildtype in presence phospho-ubiquitin and act as positive allosteric modulators (PAMs). While these activate series biochemical assays, they do not by thermally destabilizing fail to translocation rate mitochondria or enact mitophagy cell-based assays. We conclude context cellular milieu window...
Abstract Mixed Lineage Kinase domain-Like (MLKL), a key player in necroptosis, is multi-domain protein with an N-terminal 4 helical bundle (4HB) and pseudokinase domain (PsK) connected by brace helices. Phosphorylation of PsK MLKL step towards oligomerization 4HB that causes cell death. Necrosulfonamide (NSA) binds to the inhibit necroptosis. To understand molecular details function it’s inhibition, we have performed dynamic study on hMLKL apo, phosphorylated NSA-bound states for total 3 μs...
Obtaining a detailed description of how active site flap motion affects substrate or ligand binding will advance structure-based drug design (SBDD) efforts on systems including the kinases, HSP90, HIV protease, ureases, etc. Through this understanding, we be able to better inhibitors and proteins that have desired functions. Herein address issue by generating relevant configurational states protein molecular energy landscape using an approach call MTFlex-b then following with procedure...
Atomistic molecular dynamics simulations of eight selected conformations a disordered protein, amyloid beta (1-42) (Aβ), and globular ubiquitin (UBQ), have been carried out in aqueous media at 310 K. Detailed analyses were to compare the microscopic properties water molecules present hydration layers these systems. It is noticed that irrespective conformational heterogeneity among Aβ monomers, hydrating their surfaces exhibit relatively faster as compared UBQ. Importantly, monomers has found...
The rapid development of molecular structural databases provides the chemistry community access to an enormous array experimental data that can be used build and validate computational models. Using radial distribution functions collected from experimentally available X-ray NMR structures, a number so-called statistical potentials have been developed over years using mining strategy. These within context two-particle Kirkwood equation by extending its original use for isotropic monatomic...
The rank ordering of ligands remains one the most attractive challenges in drug discovery. While physics-based silico binding affinity methods dominate field, they still have problems, which largely revolve around forcefield accuracy and sampling. Recent advances machine learning gained traction for protein–ligand predictions early discovery programs. In this article, we perform retrospective free energy evaluations 172 compounds from our internal collection spread over four different...
<title>Abstract</title> Mutations in parkin and PINK1 cause early-onset Parkinson’s disease (EOPD). The ubiquitin ligase is recruited to damaged mitochondria activated by PINK1, a kinase that phosphorylates the ubiquitin-like (Ubl) domain of parkin. Activated phospho-parkin then ubiquitinates mitochondrial proteins target organelle for degradation. Here, we present mechanism activation new class small molecule allosteric modulators enhance activity. compounds act as molecular glues ability...
X-ray crystallography is the primarily technique used to determine three-dimensional (3D) structure of protein:ligand and protein:protein complexes, it plays a central role in Structure Based Drug Design (SBDD).Recently, we integrated our quantum mechanics toolkit with Phenix crystallographic package replace conventional stereochemical restraints more accurate QM/MM-based energy functional "real time" during refinement expanded this tool include density driven solvation...