9H2X

Crystal structure of stabilized A2A adenosine receptor A2AR-StaR2-bRIL in complex with compound 7, a novel nanomolar A2A receptor antagonist from modern hit-finding with structure-guided de novo design

これはPDB形式変換不可エントリーです。

9H2X の概要

• エントリーDOI: 10.2210/pdb9h2x/pdb
• 分子名称: Adenosine receptor A2a,Soluble cytochrome b562, SODIUM ION, CHOLESTEROL, ... (6 entities in total)
• 機能のキーワード: adenosine receptor, gpcr, antagonist, chemical hit, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55416.67

構造登録者

Tian, G.,Maja, N. (登録日: 2024-10-15, 公開日: 2025-06-18, 最終更新日: 2025-07-16)

主引用文献

Thomas, M.,Matricon, P.G.,Gillespie, R.J.,Napiorkowska, M.,Neale, H.,Mason, J.S.,Brown, J.,Harwood, K.,Fieldhouse, C.,Swain, N.A.,Geng, T.,O'Boyle, N.M.,Deflorian, F.,Bender, A.,de Graaf, C.
Identification of nanomolar adenosine A 2A receptor ligands using reinforcement learning and structure-based drug design.
Nat Commun, 16:5485-5485, 2025

PubMed Abstract: Generative chemical language models (CLMs) have demonstrated success in learning language-based molecular representations for de novo drug design. Here, we integrate structure-based drug design (SBDD) principles with CLMs to go from protein structure to novel small-molecule ligands, without a priori knowledge of ligand chemistry. Using Augmented Hill-Climb, we successfully optimise multiple objectives within a practical timeframe, including protein-ligand complementarity. Resulting de novo molecules contain known or promising adenosine A receptor ligand chemistry that is not available in commercial vendor libraries, accessing commercially novel areas of chemical space. Experimental validation demonstrates a binding hit rate of 88%, with 50% having confirmed functional activity, including three nanomolar ligands and two novel chemotypes. The two strongest binders are co-crystallised with the A receptor, revealing their binding mechanisms that can be used to inform future iterations of structure-based de novo design, closing the AI SBDD loop.

PubMed: 40592852
DOI: 10.1038/s41467-025-60629-0

実験手法

X-RAY DIFFRACTION (1.75 Å)