Probing Hydration Patterns in Class‑A GPCRs via Biased MD: The A2A Receptor

Herein, we present
a new computational approach for analyzing hydration
patterns in biomolecular systems. This protocol aims to efficiently
identify regions where structural waters may be located and, in the
case of protein–ligand binding, where displacing one or more
water molecules could be advantageous in terms of affinity and/or
residence time. We validated our approach on the adenosine A2A receptor, a target of significant pharmaceutical relevance. The
results of the approach are enriched with an extensive analysis of
hydration in A2A and other members of the A-family of GPCRs
using available crystallographic evidence and reviewing existing literature.
As per the protein–ligand complex case, we conducted a more
detailed study of a series of triazine analogues inhibiting A2A. The proposed approach provides results in good agreement
with existing data and offers interpretability and simple and fast
applicability.

本研究提出了一种新的计算方法，旨在分析生物分子系统中水分子的配位模式。该方案旨在高效识别可能存在结构水分子的区域，在蛋白质-配体结合的情况下，通过移除一个或多个水分子可能对亲和力及/或停留时间产生有利影响的位置。本研究方法在腺苷A2A受体上进行了验证，该受体在药物开发领域具有重要意义。通过结合可用的晶体学证据和回顾现有文献，对A2A以及其他G蛋白偶联受体家族A成员的水合作用进行了广泛分析。针对蛋白质-配体复合物的情况，我们对一系列抑制A2A的三嗪类似物进行了更为深入的研究。所提出的方法与现有数据相符良好，并提供了可解释性以及简单快捷的应用性。