A5054421536- Computational Drug Discovery Methods
- Mitochondrial Function and Pathology
- Protein Structure and Dynamics
- ATP Synthase and ATPases Research
- Receptor Mechanisms and Signaling
- Lymphoma Diagnosis and Treatment
- RNA and protein synthesis mechanisms
- Amino Acid Enzymes and Metabolism
- CAR-T cell therapy research
- Cholinesterase and Neurodegenerative Diseases
- Neuropeptides and Animal Physiology
- Pharmacological Receptor Mechanisms and Effects
- Glycosylation and Glycoproteins Research
- Adipose Tissue and Metabolism
- Metabolism, Diabetes, and Cancer
- Diabetes Treatment and Management
- Chronic Lymphocytic Leukemia Research
- Genetic and Kidney Cyst Diseases
- Alzheimer's disease research and treatments
- Advanced biosensing and bioanalysis techniques
- Vascular Malformations Diagnosis and Treatment
- Enzyme Structure and Function
- Ion Transport and Channel Regulation
- Hedgehog Signaling Pathway Studies
- Diet, Metabolism, and Disease
Vanderbilt University
2024-2025
Icahn School of Medicine at Mount Sinai
2014-2023
University of California, San Francisco
2015-2023
Vanderbilt Health
2023
Lawrence Livermore National Laboratory
2022
Italian Institute of Technology
2011-2015
Mount Sinai Hospital
2015
Scuola Superiore Internazionale di Studi Universitari di Ricerca e Formazione
2012
Istituti di Ricovero e Cura a Carattere Scientifico
2012
Ospedale Policlinico San Martino
2012
Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, development of multitarget drugs which involved both pathways might represent a promising therapeutic strategy. Accordingly, reported here is discovery 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as first class molecules able simultaneously modulate BACE-1 GSK-3β. Notably, one triazinone showed...
The multitarget approach has gained increasing acceptance as a useful tool to address complex and multifactorial maladies such Alzheimer's disease (AD). concurrent inhibition of the validated AD targets β-secretase (BACE-1) glycogen synthase kinase-3β (GSK-3β) by attacking both β-amyloid tau protein cascades been identified promising therapeutic strategy. In our study, curcumin was lead compound for simultaneous targets; therefore, synthetic efforts were dedicated obtaining small library...
The idea of sodium ions altering G-protein-coupled receptor (GPCR) ligand binding and signaling was first suggested for opioid receptors (ORs) in the 1970s subsequently extended to other GPCRs. Recently published ultra-high-resolution crystal structures GPCRs, including that δ-OR subtype, have started shed light on mechanism underlying control GPCR by revealing details site. Whether accesses different subtypes from extra- or intracellular sides, following similar pathways, is still an open...
Many pathogenic bacteria utilise sialic acids as an energy source or use them external coating to evade immune detection. As such, that colonise sialylated environments deploy specific transporters mediate import of scavenged acids. Here, we report a substrate-bound 1.95 Å resolution structure and subsequent characterisation SiaT, acid transporter from Proteus mirabilis. SiaT is secondary active the sodium solute symporter (SSS) family, which Na
Abstract Polycystin-1 (PC-1) and PC-2 form a heteromeric ion channel complex that is abundantly expressed in primary cilia of renal epithelial cells. This functions as non-selective cation channel, mutations within the polycystin cause autosomal dominant polycystic kidney disease (ADPKD). The spatial temporal regulation ciliary membrane remains poorly understood. Using both whole-cell patch-clamp recordings, we identify cilia-enriched oxysterol, 7β,27-dihydroxycholesterol (DHC), serves...
We employed a Leucine Rich Repeat Containing 8 (LRRC8) channel chimera, termed 8C-8A(IL125), to investigate the molecular mechanism of action novel volume-sensitive anion (VRAC) inhibitor, zafirlukast. 8C-8A(IL125) comprises LRRC8C (8C) and 25 residues from LRRC8A (8A) intracellular loop 1 (IL1) forms volume-sensitive, structurally defined heptameric channels with normal pharmacological properties. In silico docking modeling AlphaFold3 identified putative zafirlukast binding site comprising...
Multidrug transport by ATP binding cassette (ABC) exporters entails a mechanism to modulate drug affinity across the cycle. Here, we combine cryo-EM and molecular dynamics (MD) simulations illuminate how lipid competition modulates substrate drive its translocation ABC exporters. We determined structures of transporter BmrCD in drug-loaded inward-facing (IF) outward-facing (OF) conformations nanodiscs reveal structural basis alternating access, details drug-transporter interactions, scale...
Significance The potential energy stored in ion gradients across cell membranes drives nutrients and out of cells by cotransport proteins, e.g., uphill glucose accumulation sodium cotransporters. Insight into the mechanism has been obtained from high-resolution atomic structures transporters, but further progress requires dynamic information about substrate movements through proteins. We have used multiple long molecular-dynamic simulations electrophysiological assays to explore dynamics...
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...
With the hope of discovering effective analgesics with fewer side effects, attention has recently shifted to allosteric modulators opioid receptors. In past two years, first chemotypes positive or silent (PAMs SAMs, respectively) μ- and δ-opioid receptor types have been reported in literature. During a structure-guided lead optimization campaign μ-PAMs BMS-986121 BMS-986122 as starting compounds, we discovered new chemotype that was confirmed display μ-PAM μ-SAM activity depending on...
The voltage-dependent anion channel (VDAC) is the most abundant protein in outer mitochondrial membrane and constitutes primary pathway for exchange of ions metabolites between cytosol mitochondria. There accumulating evidence supporting VDAC's role metabolic regulation apoptosis, where VDAC oligomerization has been implicated with these processes. Herein, we report a specific pH-dependent dimerization murine VDAC1 (mVDAC1) identified by double electron-electron resonance native mass...
Mutations in Ras family proteins are implicated 33% of human cancers, but direct pharmacological inhibition mutants remains challenging. As an alternative to inhibition, we screened for sensitivities Ras-mutant cells and discovered 249C as a selective cytotoxic agent with nanomolar potency against spectrum cancers. binds vacuolar (V)-ATPase affinity inhibits its activity, preventing lysosomal acidification inhibiting autophagy macropinocytosis pathways that several Ras-driven cancers rely on...
Significance Transporters isomerize between conformations to shuttle cargo across membranes, but the mechanism is not understood. Double electron–electron resonance measurements on sodium-dependent sugar transporter (vSGLT) were used explore conformational state of under specific ligand conditions. Although transport by vSGLT driven sodium gradients, adopts an inward-open conformation irrespective presence sodium. In and galactose, transitions occluded conformation. We propose that cell’s...
Abstract Glycogen synthase kinase 3β (GSK‐3β) and casein 1δ (CK‐1δ) are emerging targets for the treatment of neuroinflammatory disorders, including Parkinson's disease. An inhibitor able to target these two kinases was developed by docking‐based design. Compound 12 , 3‐(7‐amino‐5‐(cyclohexylamino)‐[1,2,4]triazolo[1,5‐ a ][1,3,5]triazin‐2‐yl)‐2‐cyanoacrylamide, showed combined inhibitory activity against GSK‐3β CK‐1δ [IC 50 (GSK‐3β)=0.17 μ m ; IC (CK‐1δ)=0.68 ]. In particular, classical ATP...
Several neuropeptide systems in the hypothalamus, including Y and agouti-related protein (AgRP), control food intake. Peptides derived from proSAAS, a precursor implicated regulation of body weight, also GPR171 is heterotrimeric guanine nucleotide-binding (G protein)-coupled receptor (GPCR) for BigLEN (b-LEN), peptide proSAAS. To facilitate studies exploring physiological role GPR171, we sought to identify small-molecule ligands this by performing virtual screen compound library interaction...
Membrane transport is generally thought to occur via an alternating access mechanism in which the transporter adopts at least two states, accessible from different sides of membrane exchange substrates extracellular environment and cytoplasm or intracellular matrix organelles (only eukaryotes). In recent years, a number high resolution structures have supported this general framework for wide class molecules, although additional states along pathway are emerging as critically important....
Our main objective was to compile a data set of high-quality protein-fragment complexes and make it publicly available. Once assembled, the challenged using docking procedures address following questions: (i) Can molecular correctly reproduce experimentally solved structures? (ii) How thorough must sampling be replicate experimental data? (iii) commonly used scoring functions discriminate between native pose other energy minima? The set, named SERAPhiC (Selected Fragment Protein Complexes),...
In this study, we report on a virtual ligand screening protocol optimized to identify fragments endowed with activity at multiple targets. Thanks protocol, were able fragment that displays in the low-micromolar range both β-secretase 1 (BACE-1) and glycogen synthase kinase 3β (GSK-3β). These two structurally physiologically unrelated enzymes likely contribute, through different pathways, onset of Alzheimer's disease (AD). Therefore, their simultaneous inhibition holds great potential...
Motivated by growing evidence for pathway heterogeneity and alternative functions of molecular machines, we demonstrate a computational approach investigating two questions: (1) Are there multiple mechanisms (state-space pathways) which machine can perform given function, such as cotransport across membrane? (2) How additional functionality, proofreading/error-correction, be built into function using standard biochemical processes? Answers to these questions will aid both the understanding...
Abstract Motivation: A large fraction of the entries contained in Protein Data Bank describe proteins complex with low molecular weight molecules such as physiological compounds or synthetic drugs. In many cases, same molecule is found distinct protein-ligand complexes. There an increasing interest Medicinal Chemistry comparing protein binding sites to get insight on interactions that modulate specificity, this structural information can be correlated other experimental data biochemical...