Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design DOI Creative Commons
Zhengdan Zhu,

Zhenfeng Deng,

Qinrui Wang

et al.

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: June 28, 2022

Ion channels are expressed in almost all living cells, controlling the in-and-out communications, making them ideal drug targets, especially for central nervous system diseases. However, owing to their dynamic nature and presence of a membrane environment, ion remain difficult targets past decades. Recent advancement cryo-electron microscopy computational methods has shed light on this issue. An explosion high-resolution channel structures paved way structure-based rational design state-of-the-art simulation machine learning techniques dramatically improved efficiency effectiveness computer-aided design. Here we present an overview how learning-based fundamentally changed channel-related at different levels, as well emerging trends field.

Language: Английский

Structures of ferroportin in complex with its specific inhibitor vamifeport DOI Creative Commons
Elena Farah Lehmann, Márton Liziczai, Katarzyna Drożdżyk

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: March 16, 2023

A central regulatory mechanism of iron homeostasis in humans involves ferroportin (FPN), the sole cellular exporter, and peptide hormone hepcidin, which inhibits Fe

Language: Английский

Citations

9
Challenges, advances, and opportunities in RNA structural biology by Cryo-EM DOI Creative Commons
Steve Bonilla, Karen Jang

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 88, P. 102894 - 102894

Published: Aug. 8, 2024

RNAs are remarkably versatile molecules that can fold into intricate three-dimensional (3D) structures to perform diverse cellular and viral functions. Despite their biological importance, relatively few RNA 3D have been solved, our understanding of structure-function relationships remains in its infancy. This limitation partly arises from challenges posed by RNA's complex conformational landscape, characterized structural flexibility, formation multiple states, a propensity misfold. Recently, cryo-electron microscopy (cryo-EM) has emerged as powerful tool for the visualization conformationally dynamic RNA-only structures. However, characteristics continue pose challenges. We discuss experimental methods developed overcome these hurdles, including engineering modular modifications facilitate small RNAs, improve particle alignment, validate models.

Language: Английский

Citations

3
How to Find a Fragment: Methods for Screening and Validation in Fragment‐Based Drug Discovery DOI
Tim Kirkman, Catharina dos Santos Silva, Manuela Tosin

et al.

ChemMedChem, Journal Year: 2024, Volume and Issue: 19(24)

Published: Aug. 29, 2024

Abstract Fragment‐based drug discovery (FBDD) is a crucial strategy for developing new drugs that have been applied to diverse targets, from neglected infectious diseases cancer. With at least seven already launched the market, this approach has gained interest in both academics and industry last 20 years. FBDD relies on screening small libraries with about 1000–2000 compounds of low molecular weight (about 300 Da) using several biophysical methods. Because reduced size compounds, chemical space diversity can be better explored than large used high throughput screenings. This review summarises most common techniques fragment orthogonal validation. We also explore advantages drawbacks different examples applications strategies.

Language: Английский

Citations

3
Insight into the Mammalian Aquaporin Interactome DOI Open Access
Susanna Törnroth‐Horsefield, Clara Chivasso, Helin Strandberg

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 9615 - 9615

Published: Aug. 25, 2022

Aquaporins (AQPs) are a family of transmembrane water channels expressed in all living organisms. AQPs facilitate osmotically driven flux across biological membranes and, some cases, the movement small molecules (such as glycerol, urea, CO2, NH3, H2O2). Protein–protein interactions play essential roles protein regulation and function. This review provides comprehensive overview current knowledge AQP interactomes addresses molecular basis functional significance these protein–protein health diseases. Targeting may offer new therapeutic avenues targeting individual remains challenging despite intense efforts.

Language: Английский

Citations

13
Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design DOI Creative Commons
Zhengdan Zhu,

Zhenfeng Deng,

Qinrui Wang

et al.

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: June 28, 2022

Ion channels are expressed in almost all living cells, controlling the in-and-out communications, making them ideal drug targets, especially for central nervous system diseases. However, owing to their dynamic nature and presence of a membrane environment, ion remain difficult targets past decades. Recent advancement cryo-electron microscopy computational methods has shed light on this issue. An explosion high-resolution channel structures paved way structure-based rational design state-of-the-art simulation machine learning techniques dramatically improved efficiency effectiveness computer-aided design. Here we present an overview how learning-based fundamentally changed channel-related at different levels, as well emerging trends field.

Language: Английский

Citations

10