We used an MC2R conformational ensemble to represent the receptor consisting of the activated MC2R domain of the ACTH:MC2R:MRAP1:Gs complex , the MC2R AlphaFold model, and a homology model based on an MC4R crystal structure (Supporting Information). The screening site included residues I84, E80, K77, D103, I106, D107, S108, F110, L112, V111, L114, V166, F178, W232, F235, F258, I265. (Fig ). We used HE and NGT to screen the site. To improve the diversity of hits from HE we slightly modified the algorithm (Methods). Importantly, the training data for NGT did not contain MC2R antagonists.