A MULTISCALE APPROACH TO TARGET THE ACHILLES HEEL OF P53 CANCER MUTANTS

针对 P53 癌症突变体致命弱点的多尺度方法

基本信息

批准号：
10391499
负责人：
Rommie E Amaro
金额：
$ 31.17万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-05 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10391499
关键词：
Architecture Binding Binding Proteins Binding Sites Biological Assay Cell Survival Chemicals Closure by clamp Complex Computer Simulation Computing Methodologies DNA DNA Binding DNA Sequence Detection Deuterium Development Feedback Goals Human Hydrogen Individual Length Ligands Malignant Neoplasms Membrane Proteins Methodology Methods Modeling Molecular Conformation Motion Mutate Mutation Outcome Papillomavirus Transforming Protein E6 Pharmaceutical Preparations Point Mutation Protein Dynamics Proteins Response Elements Signal Transduction Signaling Protein Structure System TP53 gene Testing Therapeutic Time Translations Tumor Suppressor Proteins Viral Proteins Work base cost data exchange drug discovery falls lead optimization molecular dynamics mutant novel novel strategies protein structure screening simulation small molecule theories therapeutic target transcription factor tumor progression viral DNA viral rescue virtual screening

项目摘要

SUMMARY p53 is arguably one of the most important tumor suppressor proteins in humans. In almost 50% of all human cancers, p53 is found to be nonfunctional mostly due to single point mutations. The primary goals of this proposal are to gain a detailed understanding of the effect of most-frequent p53 cancer mutations on the protein structure and dynamics, and to leverage a novel computational methodology that identifies small molecules able to reactivate destabilized p53 cancer mutants—a method that represents a promising new approach to drug discovery. We aim to extend our understanding of the structural dynamics of truncated and full-length p53 with state- of-the-art molecular dynamics simulations in order to discovery novel druggable pockets that have not yet been experimentally characterized. Subsequently we plan to use this new structural information to identify small molecules with novel mechanisms of action and reveal new potential therapeutic avenues targeting this vital transcription factor.

概括 p53可以说是人类中最重要的肿瘤抑制蛋白之一。在几乎50％在所有人类癌症中，发现p53主要是由于单点突变引起的。该提案的主要目标是详细了解最频繁的影响 p53蛋白质结构和动力学上的癌症突变，并利用新颖鉴定小分子可以重新激活不稳定的p53的计算方法论癌症突变体 - 一种代表一种有前途的药物发现方法的方法。我们的目标为了扩展我们对具有状态的截短和全长p53的结构动力学的理解艺术分子动力学模拟的尚未实验表征。随后，我们计划使用这种新结构信息以识别具有新型作用机理的小分子并揭示了新的潜力针对此重要转录因子的治疗途径。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DeepWEST: Deep Learning of Kinetic Models with the Weighted Ensemble Simulation Toolkit for Enhanced Sampling.

DOI：
10.1021/acs.jctc.2c00282
发表时间：
2023-01
期刊：
Journal of chemical theory and computation
影响因子：
5.5
作者：
Anupam Anand Ojha;Saumya Thakur;Surl-Hee Ahn;Rommie E. Amaro
通讯作者：
Anupam Anand Ojha;Saumya Thakur;Surl-Hee Ahn;Rommie E. Amaro

A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors.

DOI：
10.1016/j.bpj.2021.01.037
发表时间：
2021-03-16
期刊：
Biophysical journal
影响因子：
3.4
作者：
Oliveira ASF;Ibarra AA;Bermudez I;Casalino L;Gaieb Z;Shoemark DK;Gallagher T;Sessions RB;Amaro RE;Mulholland AJ
通讯作者：
Mulholland AJ

An integrated view of p53 dynamics, function, and reactivation.

p53 动态、功能和重新激活的综合视图。