Structure-based discovery of potent and selective melatonin receptor agonists

Abstract

Melatonin receptors MT1 and MT2 are involved in synchronizing circadian rhythms and are important targets for treating sleep and mood disorders, type-2 diabetes and cancer. Here, we performed large scale structure-based virtual screening for new ligand chemotypes using recently solved high-resolution 3D crystal structures of agonist-bound MT receptors. Experimental testing of 62 screening candidates yielded the discovery of 10 new agonist chemotypes with sub-micromolar potency at MT receptors, with compound 21 reaching EC50 of 0.36 nM. Six of these molecules displayed selectivity for MT2 over MT1. Moreover, two most potent agonists, including 21 and a close derivative of melatonin, 28, had dramatically reduced arrestin recruitment at MT2, while compound 37 was devoid of Gi signaling at MT1, implying biased signaling. This study validates the suitability of the agonist-bound orthosteric pocket in the MT receptor structures for the structure-based discovery of selective agonists.

Melatonin receptor ligands: A pharmaco‐chemical perspective

“…As previously mentioned, 18 the landscape of receptor molecular pharmacology—particularly melatonin receptors—became even more complex due to the lack of selective antibodies (until recently 156 ) and the complex nature of biasism 19 . The melatonin receptor crystallization works of Stauch et al on MT 1 125 and of Johansson et al on MT 2 126 open new and exciting avenues of research regarding this bicycle motto, which has already begun 135,136 …”

“…Interestingly, DIV880 is one of the few high‐affinity compounds belonging to a different chemotype among approximately 2000 “classical” melatonergic ligands that were designed based on melatonin structure (see Table 1 for chemical family details). Only very recently, new, mostly MT 2 ‐ but also MT 1 ‐selective agonists of novel chemotypes have been discovered by virtual screening of the ZINC database using the MT 1 and MT 2 crystal structures 135,136 (see discussion in Section 9).…”

“…The newly described high‐resolution MT 1 and MT 2 crystal structures 125,126 are expected to help in the discovery of ligands with new chemotypes using methods of structure‐based drug design 155 . Indeed, virtual screening of the ZINC database has led to the recent discovery of potent and selective melatonin receptor agonists and partial agonists 135,136 …”

“…Another ligand with a unique pharmacological profile is compound 58 , a low‐affinity functionally MT 2 ‐selective partial agonist characterized by biased signaling at MT 1 receptors showing only β‐arrestin activity with complete lack of G protein signaling. The lack of G i ‐mediated signaling at MT 1 receptors has been explained by a missing hydrogen bond to Asn162, an interaction which seems to have no effect on MT 1 β‐arrestin signaling 136 …”

State of the Art Iterative Docking with Logistic Regression and Morgan Fingerprints

“…Large-scale docking campaigns have consistently demonstrated the ability to identify in vitro hits with novel scaffolds (21)(22)(23)(24)(25)(26). Nevertheless, the computation demands for ultra-large campaigns are substantial, typically being associated with high-performance computing clusters (5)(6)(7).…”