A5051041892- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Spectroscopy and Quantum Chemical Studies
- Advanced Chemical Physics Studies
- Laser-Matter Interactions and Applications
- Fatty Acid Research and Health
- Spectroscopy and Laser Applications
- Eicosanoids and Hypertension Pharmacology
- Microbial Natural Products and Biosynthesis
- Inflammatory mediators and NSAID effects
- Chemical Synthesis and Analysis
- Quantum, superfluid, helium dynamics
- Electron Spin Resonance Studies
- Bioactive Compounds and Antitumor Agents
- Analytical Chemistry and Chromatography
- Synthesis and Biological Evaluation
- Receptor Mechanisms and Signaling
- Diabetes Treatment and Management
- Glycosylation and Glycoproteins Research
- Spectroscopy Techniques in Biomedical and Chemical Research
- Heat shock proteins research
- Peroxisome Proliferator-Activated Receptors
- Pharmacogenetics and Drug Metabolism
- Estrogen and related hormone effects
University of California, San Francisco
2011-2023
University of California System
2016-2021
QB3
2009-2014
University of California, Santa Cruz
2006
Albert Einstein College of Medicine
2002
University of New Mexico
2000-2002
University of Massachusetts Amherst
1999
University College London
1998-1999
Indian Institute of Technology Kanpur
1993-1997
We report an atomistic physical model for the passive membrane permeability of cyclic peptides. The computational modeling was performed in advance experiments and did not involve use "training data". explicitly treats conformational flexibility peptides by extensive sampling low (membrane) high (water) dielectric environments. permeabilities 11 were obtained experimentally using a parallel artificial assay (PAMPA) showed linear correlation with results R(2) = 0.96. In general, support...
Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α
Cancer cells rely on the chaperone heat shock protein 70 (Hsp70) for survival and proliferation. Recently, benzothiazole rhodacyanines have been shown to bind an allosteric site Hsp70, interrupting its binding nucleotide-exchange factors (NEFs) promoting cell death in breast cancer lines. However, proof-of-concept molecules, such as JG-98, relatively modest potency (EC50 ≈ 0.7-0.4 μM) are rapidly metabolized animals. Here, we explored this chemical series through structure- property-based...
We demonstrate that using an all-atom molecular mechanics force field combined with implicit solvent model for scoring protein−ligand complexes is a promising approach improving inhibitor enrichment in the virtual screening of large compound databases. The rescoring method evaluated by extent to which known binders nine diverse, therapeutically relevant enzymes are enriched against background ∼100 000 drug-like decoys. improvement most robust and dramatic within top 1% ranked database, is,...
Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets Sec61 translocon and selectively disrupts secretory membrane in signal peptide-dependent manner. KZR-8445 potently inhibits secretion pro-inflammatory cytokines primary immune cells highly efficacious mouse model rheumatoid arthritis. A cryogenic...
Cryptosporidiosis, caused by the protozoan parasite Cryptosporidium parvum, can stunt infant growth and be lethal in immunocompromised individuals. The most widely used drugs for treating cryptosporidiosis are nitazoxanide paromomycin, although both exhibit limited efficacy. To investigate an alternative approach to therapy, we demonstrate that clan CA cysteine protease inhibitor N-methyl piperazine-Phe-homoPhe-vinylsulfone phenyl (K11777) inhibits C. parvum mammalian cell lines a...
We introduce the "Prime-ligand" method for ranking ligands in congeneric series. The employs a single scoring function, OPLS-AA/GBSA molecular mechanics/implicit solvent model, all stages of sampling and scoring. evaluate using 12 test sets series which experimental binding data is available literature, as well structure one member bound to protein. Ligands are "docked" by superimposing common stem fragment among compounds crystal complex from Protein Data Bank conformational space variable...
The rapid advance in genome sequencing presents substantial challenges for protein functional assignment, with half or more of new sequences inferred from these genomes having uncertain assignments. assignment enzyme function functionally diverse superfamilies represents a particular challenge, which we address through combination computational predictions, enzymology, and structural biology. Here describe the results focused investigation group enzymes enolase superfamily that are involved...
Schistosoma flatworm parasites cause schistosomiasis, a chronic and debilitating disease of poverty in developing countries. Praziquantel is employed for treatment control. However, its efficacy spectrum incomplete (less active or inactive against immature stages the parasite) there concern drug resistance. Thus, need to identify new drugs targets.We show that RNA interference (RNAi) mansoni ortholog human polo-like kinase (huPLK)1 elicits deleterious phenotypic alteration post-infective...
The two oxylipins 7S,14S-dihydroxydocosahexaenoic acid (diHDHA) and 7S,17S-diHDHA [resolvin D5 (RvD5)] have been found in macrophages infectious inflammatory exudates are believed to function as specialized pro-resolving mediators (SPMs). Their biosynthesis is thought proceed through sequential oxidations of DHA by lipoxygenase (LOX) enzymes, specifically, human 5-LOX (h5-LOX) first 7(S)-hydroxy-4Z,8E,10Z,13Z,16Z,19Z-DHA (7S-HDHA), followed platelet 12-LOX (h12-LOX) form...
We have developed a virtual ligand screening method designed to help assign enzymatic function for alpha−beta barrel proteins. dock library of ∼19,000 known metabolites against the active site and attempt identify relevant substrate based on predicted relative binding free energies. These energies are computed using physics-based energy an all-atom force field (OPLS-AA) generalized Born implicit solvent model. evaluate ability this substrates several members enolase superfamily enzymes,...
Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due their role in renal sugar reabsorption, SGLTs are targets for treatment of type 2 diabetes. Current therapeutics phlorizin derivatives that contain a moiety bound an aromatic aglycon tail. Here, we develop structural models human SGLT1/2 complex with inhibitors by combining computational and functional studies. Inhibitors bind pocket tail extracellular vestibule. The...
Protein–protein interactions (PPIs) are an important category of putative drug targets. Improvements in high-throughput screening (HTS) have significantly accelerated the discovery inhibitors for some categories PPIs. However, methods suitable multiprotein complexes (e.g. those composed three or more different components) been slower to emerge. Here, we explored approach that uses reconstituted (RMPCs). As a model system, chose heat shock protein 70 (Hsp70), which is ATP-dependent molecular...
Human reticulocyte 15-lipoxygenase-1 (h15-LOX-1 or ALOX15) and platelet 12-lipoxygenase (h12-LOX ALOX12) catalysis of docosahexaenoic acid (DHA) the maresin precursor, 14S-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic (14S-HpDHA), were investigated to determine their product profiles relative rates in biosynthesis key intermediate, 13S,14S-epoxy-4Z,7Z,9E,11E,16Z,19Z-docosahexaenoic (13S,14S-epoxy-DHA). Both enzymes converted DHA 14S-HpDHA, with h12-LOX having a 39-fold greater kcat/KM...
The structure of an uncharacterized member the enolase superfamily from Oceanobacillus iheyensis (GI 23100298, IMG locus tag Ob2843, PDB entry 2OQY ) was determined by New York SGX Research Center for Structural Genomics (NYSGXRC). contained two Mg(2+) ions located 10.4 A one another, with in canonical position (beta/alpha)(7)beta-barrel domain (although ligand at end fifth beta-strand is His, unprecedented structurally characterized members superfamily); second a novel site within capping...
Lipoxygenase (LOX) enzymes catalyze the hydroperoxidation of arachidonic acid and other polyunsaturated fatty acids to hydroxyeicosatetraenoic with varying positional specificity yield important biological signaling molecules. Human epithelial 15lipoxygenase2 (15-LOX-2) is a highly specific LOX isozyme that expressed in tissue whose activity has been correlated suppression tumor growth prostate derived cancers. Despite potential utility an inhibitor probe role 15-LOX-2 progression, no such...
In this paper, human platelet 12-lipoxygenase [h12-LOX (ALOX12)], reticulocyte 15-lipoxygenase-1 [h15-LOX-1 (ALOX15)], and epithelial 15-lipoxygenase-2 [h15-LOX-2 (ALOX15B)] were observed to react with docosahexaenoic acid (DHA) produce 17S-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic (17S-HpDHA). The kcat/KM values DHA for h12-LOX, h15-LOX-1, h15-LOX-2 12, 0.35, 0.43 s–1 μM–1, respectively, which demonstrate h12-LOX as the most efficient of three. These are comparable their counterpart...