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). In the work, we utilized extensive Gaussian-accelerated molecular dynamics simulations (a total of 41μs) for the first time probe the diverse binding modes of the allosteric modulator and their regulation effects, based on the DRD1 and LY3154207 as representative. Our simulations identify four binding modes of LY3154207 (one boat mode, two metastable vertical modes and a novel cleft-anchored mode), in which the boat mode is the most stable while there three modes are similar in the stability. However, it is interesting to observed that the most stable boat mode inversely exhibits the weakest positive allosteric effect on influencing the orthosteric ligand binding and maintaining the activity of the transducer binding site. It should result from its induced weaker correlation between the allosteric site and the orthosteric site, and between the orthosteric site and the transducer binding site than the other three binding modes, as well as its weakened interaction between a crucial activation-related residue (S2025.46) and the orthosteric ligand (dopamine). Overall, the work offers atomic-level information to advance our understanding of the complex allosteric regulation on GPCRs, which is beneficial to the allosteric modulator design and development.