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Computational tools to aid the design of glycomimetic agents

帮助设计糖模拟剂的计算工具

基本信息

批准号：
10477037
负责人：
ROBERT J WOODS
金额：
$ 37.43万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10477037
关键词：
Address Adhesions Affinity Antibiotics Antiviral resistance Bacteria Bacterial Adhesins Binding Binding Sites Biological Carbohydrates Cations Cell Membrane Permeability Cell surface Cells Chemical Structure Chemicals Complex Computer Models Crystallization DNA Sequence Alteration Data Development Diarrhea Disease Docking Down-Regulation Drug Targeting Endocytosis Ensure Enzymes Evaluation Familiarity Food Poisoning Glycoside Hydrolases Hemagglutinin Human Hydrogen Bonding Hydrophobicity In Situ Infection Informatics Intention Intestines Lectin Libraries Ligands Mainstreaming Mediating Membrane Fusion Methods Modeling Modification Molecular Conformation Mucous Membrane Multiple Bacterial Drug Resistance Nomenclature Oligosaccharides Pathogenicity Pharmaceutical Chemistry Pharmaceutical Preparations Polysaccharides Positioning Attribute Property Protein-Carbohydrate Interaction Proteins Reporting Role Salmonella Scheme Scientist Seminal Sialic Acids Site Specificity Structure Technology Testing Therapeutic Therapeutic Agents Therapeutic Intervention Up-Regulation Validation Variant Viral War Water analog base carbohydrate analog carbohydrate binding protein carbohydrate structure chemical property computerized tools design experience experimental group glycomimetics glycosyltransferase hydroxyl group improved influenzavirus inhibitor lead optimization nanomolar novel therapeutics pathogen protein complex scaffold screening simulation small molecule inhibitor structural biology targeted treatment tool van der Waals force virtual screening web based interface

项目摘要

Project Summary Specific interactions between carbohydrates (also known as glycans) and proteins underlie the initiation or progression of many diseases. Carbohydrate-binding proteins (human, bacterial or viral lectins and adhesins) and carbohydrate-processing enzymes (glycosyltransferases and glycosidases) are therefore important targets for therapeutic intervention, however the creation of drug-like molecules that can competitively inhibit carbohydrate-binding sites is uniquely challenging. The optimization of a glycomimetic inhibitor involves the synthesis and screening of chemical analogs in an attempt to increase the inhibitory potential and biological activity. Given that carbohydrate synthesis is notoriously laborious, the task of evaluating innumerable analogs with incrementally increasing affinities introduces a particularly significant bottleneck for glycomimetic development. Despite the challenges, the benefit of employing the native carbohydrate as a scaffold is that it intrinsically confers the desired specificity. The fundamental challenge in the creation of a glycomimetic is that of divining which modifications will lead to enhanced affinity without compromising specificity. Computational approaches that are specifically designed to screen analogs of carbohydrates could be invaluable aids to both increasing the objectivity of the synthetic choices and to prioritizing the synthetic effort required for glycomimetic development. Virtual screening is commonplace in mainstream medicinal chemistry and has led to the discovery of non-glycomimetic small molecule inhibitors with nanomolar affinities (12,29). However, it has yet to be widely applied in glycomimetic design. We believe that this is due to several factors, including the complexity of carbohydrate structure and nomenclature, which creates a significant barrier for non-glycoscientists, and, for glycoscientists, a lack of familiarity with sophisticated modeling methods. In the present application, we propose to develop, validate, and implement an alternative strategy to ligand docking that leverages the benefits of computational modeling and structural biology. Specifically, we will develop an online computational approach that uses carbohydrate-protein co-crystal (or NMR) structures as the basis for lead optimization by modifying the bound oligosaccharide in situ. We have assembled a group of experimental glycobiologists and chemists who have agreed to provide data and independently validate the predictive accuracy of the tools we are developing. These scientists have over 200 years of combined experience in glycomimetic synthesis and evaluation. Successful completion of the aims will lead to a validated computational tool to aid in the discovery and optimization of therapeutic agents that target carbohydrate-protein interactions that are particularly relevant in the ongoing battle against multidrug resistant bacteria.

项目总结

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Position-specific N- and O-glycosylation of the reactive center loop impacts neutrophil elastase-mediated proteolysis of corticosteroid-binding globulin.

DOI：
10.1016/j.jbc.2023.105519
发表时间：
2024-01
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Chernykh, Anastasia;Abrahams, Jodie L;Grant, Oliver C;Kambanis, Lucas;Sumer-Bayraktar, Zeynep;Ugonotti, Julian;Kawahara, Rebeca;Corcilius, Leo;Payne, Richard J;Woods, Robert J;Thaysen-Andersen, Morten
通讯作者：
Thaysen-Andersen, Morten

Protein-Ligand CH-π Interactions: Structural Informatics, Energy Function Development, and Docking Implementation.