Ron Dror - US grants
Affiliations: | D. E. Shaw Research, New York, NY, United States | ||
| Computer Science | Stanford University, Palo Alto, CA |
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The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, Ron Dror is the likely recipient of the following grants.| Years | Recipients | Code | Title / Keywords | Matching score |
|---|---|---|---|---|
| 2018 — 2021 | Dror, Ron | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Discovering the Mechanism of Gpcr-Mediated Arrestin Stimulation to Enable Effective Drug Therapies @ Stanford University Project Summary Medicines that cause G protein?coupled receptors (GPCRs) to selectively stimulate arrestins, or to selectively avoid stimulation of arrestins, promise more effective and safer treatments for a wide variety of diseases, including neuropsychiatric, cardiovascular, pulmonary and metabolic disorders. Despite intense study of GPCR?arrestin interactions in both academia and the pharmaceutical industry, and despite dramatic recent advances in the structural biology of GPCRs and arrestins, the mechanism by which GPCRs stimulate arrestins remains poorly understood. Likewise, the means by which GPCRs might achieve selectivity for or against arrestin signaling remains unclear. The proposed research will utilize atomic-level molecular dynamics simulations to address these challenges, thereby providing a foundation for the design of functionally selective GPCR-targeted drugs with desired effects on arrestins. Aim 1 is to determine the activation mechanism of arrestin, pinpointing which of the GPCR? arrestin interaction surfaces drives arrestin activation and discovering the allosteric coupling between regions of arrestin that causes these structural changes to take place. The remaining aims are to determine the effect of both GPCR conformation (Aim 2) and GPCR phosphorylation pattern (Aim 3) on arrestin binding and activation. This will reveal how a GPCR can favor or disfavor arrestin recruitment and signaling relative to G protein recruitment and signaling. It will also reveal how a GPCR can favor specific arrestin conformations, potentially stimulating some of arrestin?s downstream effects without stimulating others. The proposed research will rely on state-of-the-art simulation methods that have recently enabled the determination of functional mechanisms of GPCRs, G proteins, transporters, and other proteins. It will also benefit from close collaborations with multiple experimentalists: results from crystallography, fluorescence spectroscopy, NMR, electron paramagnetic resonance, and cell signaling experiments will combine to both guide and validate the simulations. This proposal is significant not only because it will illuminate a quintessential biological signaling process but also because it will reveal a key part of the structural basis for functional selectivity at GPCRs. It will thus provide a foundation for the rational design of safer and more effective medications acting at GPCRs, which are by far the largest class of drug targets. |
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| 2021 | Dror, Ron Gereau, Robert W (co-PI) [⬀] Majumdar, Susruta |
R34Activity Code Description: To provide support for the initial development of a clinical trial or research project, including the establishment of the research team; the development of tools for data management and oversight of the research; the development of a trial design or experimental research designs and other essential elements of the study or project, such as the protocol, recruitment strategies, procedure manuals and collection of feasibility data. |
Synthesis of Peripherally Active Cb1 Agonists as Analgesics @ St. Louis College of Pharmacy ABSTRACT Opioid use disorders (OUD) are responsible for a major health and socioeconomic crisis in the US, resulting in more than $500B burden on the economy and more than 47,000 deaths a year due to opioid overdose. More than 80% of OUD cases started from the use of prescription opioid painkillers, which is currently the most effective (and often the only available) option for treatment of severe pain. The current analgesics target ?-Opioid receptor (MOR), which mediates not only analgesia but also dependence, addiction leading to OUD, as well as respiratory depression and death. Diversion and misuse of prescription opioid drugs in US is the key reason for the skyrocketing opioid epidemic. Development of a new generation of safe and effective analgesics with diminished addiction and abuse potential is desperately needed. We propose to target peripheral cannabinioid receptor subtype 1 (CB1) as a mechanism to develop pain relievers devoid of the addiction potential associated with opioid receptors as well as centrally active CB1 agonists. We propose a bitopic approach targeting the orthosteric site of CB1 to achieve potency and efficacy and allosteric sodium binding pocket to achieve peripheral over central activity in vivo. Our long term goal is to develop an orally active CB1 selective agonist with nM potency, poor brain penetration with optimal drug like properties like protein binding, metabolic stability, no hERG, CYP liability and oral activity, a goal we will seek to achieve through the U19 mechanism this R34 feeds into. ADME and PK fine tuning on leads obtained through R34 will be a part of the U19 phase of development. For this R34 planning grant we bring together a multidisciplinary team with the aim to test if the bitopic approach can lead to compounds with efficacy in animal models of pain and highly restricted peripheral activity while showing selectivity for CB1 receptors. Our optimal compound to be synthesized through this R34 phase will be have the following characteristics: 1) In vitro profile: CB1-agonist with ?50 nM potency and 100 fold selectivity over other >350 other targets. 2) DMPK profile: Protein binding<5% free at 10 µM, metabolic stability>2h, hERG>10 µM, CYP inhibition/activation <20-30% at 10µM and brain:plasma <0.03. 3) In vivo profile: IP/Oral CB1 mediated analgesic, potency ED50?5-10 mg/mg with >2.5h analgesic time course and lacking central side-effects like abuse potential and other liabilities upto 15xED50 doses. |
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