A5023020517- Nicotinic Acetylcholine Receptors Study
- Ion channel regulation and function
- Receptor Mechanisms and Signaling
- Protein Structure and Dynamics
- Click Chemistry and Applications
- Computational Drug Discovery Methods
- RNA and protein synthesis mechanisms
- Chemical Synthesis and Analysis
- Venomous Animal Envenomation and Studies
- Monoclonal and Polyclonal Antibodies Research
- Lipid Membrane Structure and Behavior
- Genetics, Bioinformatics, and Biomedical Research
- Neuroscience and Neuropharmacology Research
- Neuroscience and Neural Engineering
- Cholinesterase and Neurodegenerative Diseases
- Mass Spectrometry Techniques and Applications
- Neurobiology and Insect Physiology Research
- Estrogen and related hormone effects
- Crystallography and molecular interactions
- Menopause: Health Impacts and Treatments
- Computational Physics and Python Applications
- Stress Responses and Cortisol
- Amino Acid Enzymes and Metabolism
Schrodinger (United States)
2020-2025
D. E. Shaw Research
2011-2022
New York University
2016-2019
Hunter College
2016
City University of New York
2016
Icahn School of Medicine at Mount Sinai
2006
The mechanism of ion channel voltage gating-how channels open and close in response to changes-has been debated since Hodgkin Huxley's seminal discovery that the crux nerve conduction is flow across cellular membranes. Using all-atom molecular dynamics simulations, we show how a voltage-gated potassium (KV) switches between activated deactivated states. On deactivation, pore hydrophobic collapse rapidly halts flow. Subsequent voltage-sensing domain (VSD) relaxation, including inward,...
Long-term cyclic treatment with 17beta-estradiol reverses age-related impairment in ovariectomized rhesus monkeys on a test of cognitive function mediated by the prefrontal cortex (PFC). Here, we examined potential neurobiological substrates this effect using intracellular loading and morphometric analyses to possibility that benefits hormone are associated structural plasticity layer III pyramidal cells PFC area 46. 17beta-Estradiol did not affect several parameters such as total dendritic...
Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that central to virtually all aspects of cellular function. Identifying small molecules modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design drugs disrupt challenging, however, because many potential drug-binding sites at PPI interfaces “cryptic”: When unoccupied by ligand, cryptic often flat and featureless, thus not readily recognizable in crystal structures, the...
Significance Predicting how conotoxins bind to nicotinic acetylcholine receptors (nAChRs) is hard. Not only are these venom-derived peptides large, but the structures of many nAChRs unknown. In response, we developed an ensemble-docking algorithm named ToxDock. We used ToxDock reliably dock conotoxin α-GID a homology model α4β2 nAChR, main nAChR in brain and target for nicotine addiction therapeutics. A virtual screen with identified four analogs and, based on experimental evidence,...
The lead optimization stage of a drug discovery program generally involves the design, synthesis, and assaying hundreds to thousands compounds. design phase is usually carried out via traditional medicinal chemistry approaches and/or structure-based (SBDD) when suitable structural information available. Two major limitations this approach are (1) difficulty in rapidly designing potent molecules that adhere myriad project criteria, or multiparameter (MPO) problem, (2) relatively small number...
Small molecules that bind the Son of Sevenless 1 protein (SOS1), thereby preventing activation RAS, have been widely pursued as a means for cell proliferation inhibition and antitumor activity. Guided by free-energy perturbation (FEP+) simulations, we discovered two acidic residues on perimeter known small molecule binding site SOS1, E906 E909, constitute potency handle can improve inhibitor affinity much 750-fold when targeted with basic groups to form salt bridges, despite being solvent...
We report on the development and validation of OPLS5 force field. further extends accuracy our previous model (OPLS4) with addition explicit polarization to improve for molecular ions cation-pi interactions. also includes advances functional form metals achieving significant improvements across benchmarks assessing structure energetics metal-organic complexes. Together these lead improved protein-ligand binding benchmarks.
Nicotinic acetylcholine receptor (nAChR) subtypes are key drug targets, but it is challenging to pharmacologically differentiate between them because of their highly similar sequence identities. Furthermore, α-conotoxins (α-CTXs) naturally selective and competitive antagonists for nAChRs hold great potential treating nAChR disorders. Identifying selectivity-enhancing mutations the chief aim most α-CTX mutagenesis studies, although doing so with traditional docking methods difficult due lack...
Small-molecule antivirals that prevent the replication of SARS-CoV-2 virus by blocking enzymatic activity its main protease (Mpro) are and will be a tenet pandemic preparedness. However, peptidic nature such compounds often precludes design within favorable physical property ranges, limiting cellular activity. Here we describe discovery peptide aldehyde Mpro inhibitors with potent antiviral This structure-activity relationship (SAR) exploration was guided use calculated hydration site...
Gating modifier toxins (GMTs) isolated from venomous organisms such as Protoxin-II (ProTx-II) and Huwentoxin-IV (HwTx-IV) that inhibit the voltage-gated sodium channel NaV1.7 by binding to its voltage-sensing domain II (VSDII) have been extensively investigated non-opioid analgesics. However, reliably predicting how a mutation GMT will affect potency for has challenging. Here, we hypothesize structure-based computational methods can be used predict changes. We employ free-energy perturbation...
Abstract Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that central to virtually all aspects of cellular function. Identifying small molecules modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design drugs disrupt challenging, however, because many potential drug-binding sites at PPI interfaces “cryptic”: When unoccupied by ligand, cryptic often flat and featureless, thus not readily recognizable in crystal...
Nicotinic acetylcholine receptor (nAChR) ligands that lack agonist activity but enhance activation in the presence of an are called positive allosteric modulators (PAMs). nAChR PAMs have therapeutic potential for treatment nicotine addiction and several neuropsychiatric disorders. need to be selectively targeted toward certain subtypes tap this potential. We previously discovered a novel PAM, (R)-7-bromo-N-(piperidin-3-yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which potentiates opening...
Understanding the determinants of α-conotoxin (α-CTX) selectivity for different nicotinic acetylcholine receptor (nAChR) subtypes is a prerequisite design tool compounds to study nAChRs. However, optimization these small, disulfide-rich peptides difficult not only because an absence α-CTX/nAChR co-structures but also it challenging predict how mutation α-CTX will alter its potency and selectivity. As prototypical system investigate selectivity, we employed LvIA that 25-fold selective α3β2...
Peptide toxins isolated from venomous creatures, long prized as research tools due to their innate potency for ion channels, are emerging drugs well. However, it remains challenging understand why peptide bind with high identify residues that key activity, and improve affinities via mutagenesis. We use WaterMap, a molecular dynamics simulation-based method, gain computational insight into these three questions by calculating the locations thermodynamic properties of water molecules in toxin...
Understanding the determinants of α-conotoxin (α-CTX) selectivity for different nicotinic acetylcholine receptor (nAChR) subtypes is a requisite design tool compounds to study nAChRs. However, optimization these small, disulfide rich peptides difficult not only because an absence α-CTX/nAChR co-structures, but also it challenging predict how mutation α-CTX will alter its potency and selectivity. As prototypical system investigate selectivity, we employed LvIA that 18-fold selective α3β2...
Understanding the determinants of α-conotoxin (α-CTX) selectivity for different nicotinic acetylcholine receptor (nAChR) subtypes is a requisite design tool compounds to study nAChRs. However, optimization these small, disulfide rich peptides difficult not only because an absence α-CTX/nAChR co-structures, but also it challenging predict how mutation α-CTX will alter its potency and selectivity. As prototypical system investigate selectivity, we employed LvIA that 18-fold selective α3β2...
The lead optimization stage of a drug discovery program generally involves the design, synthesis and assaying hundreds to thousands compounds. design phase is usually carried out via traditional medicinal chemistry approaches and/or structure based (SBDD) when suitable structural information available. Two major limitations this approach are (1) difficulty in rapidly designing potent molecules that adhere myriad project criteria, or multiparameter (MPO) problem, (2) relatively small number...
The Pingry School's 2010–2011 S.M.A.R.T. (Students Modeling A Research Topic) Team worked with Abba E. Leffler and Willy Wriggers of D.E. Shaw (DESRES) to explore the phenomenon protein folding. Researchers at DESRES utilized molecular dynamics (MD) in combination Anton supercomputer generate simulations fastest folding WW domain reported date, FiP35 (Shaw et al. 2010). Anton's ability predict trajectories atoms that constitute a molecule resulted discovery FiP35's tendency follow...