Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR.

Allosteric drugs offer a new avenue for modern drug design. However, the identification of cryptic allosteric sites presents a formidable challenge. Following the allostery nature of residue-driven conformation transition, we propose a state-of-the-art computational pipeline by developing a residue-intuitive hybrid machine learning (RHML) model coupled with molecular dynamics (MD) simulation, through which we can efficiently identify the allosteric site and allosteric modulator as well as reveal their regulation mechanism.

Computational insights into diverse binding modes of the allosteric modulator and their regulation on dopamine D1 receptor.

Allosteric drugs hold the promise of addressing many challenges in the current drug development of GPCRs. However, the molecular mechanism underlying their allosteric modulations remain largely elusive. The dopamine D1 receptor (DRD1), a member of Class A GPCRs, is critical for treating psychiatric disorders, and LY3154207 serves as its promising positive allosteric modulator (PAM).

Exploring biased activation characteristics by molecular dynamics simulation and machine learning for the μ-opioid receptor.

Biased ligands selectively activating specific downstream signaling pathways (termed as biased activation) exhibit significant therapeutic potential. However, the conformational characteristics revealed are very limited for the biased activation, which is not conducive to biased drug development. Motivated by the issue, we combine extensive accelerated molecular dynamics simulations and an interpretable deep learning model to probe the biased activation features for two complex systems constructed by the inactive μOR and two different biased agonists (G-protein-biased agonist TRV130 and β-arrestin-biased agonist endomorphin2).

A fast response time gas ionization chamber detector with a grid structure.

The time response characteristic of the detector is crucial in radiation imaging systems. Unfortunately, existing parallel plate ionization chamber detectors have a slow response time, which leads to blurry radiation images. To enhance imaging quality, the electrode structure of the detector must be modified to reduce the response time.