The potential endocrine-disrupting properties of cyanotoxins, such as microcystin-LR (MC-LR) and cylindrospermopsin (CYN), are of concern due to their increasing occurrence, insufficient body of research, and potential impact on human health. Thus, an in silico procedure to assess the potential ability of MC-LR and CYN to form stable complexes with the estrogen receptor (ER) and the androgen receptor (AR) was performed for the first time. For that purpose, the molecular docking of both toxins was carried out. Ligand structures were generated in ChemDraw and subsequently docked against four distinct crystal structures of the ER and additional crystal structures of the AR. AutoDock was employed for docking to predict the potential agonist or antagonist activity of the toxins. The molecular docking of MC-LR and CYN with ER conformations revealed potential binding interactions. MC-LR exhibited a stronger affinity for the agonist conformations (1ERE: -7.1 kcal/mol; 3ERD: -8.2 kcal/mol) compared to the antagonist conformations (1ERR: -6.4 kcal/mol; 3ERT: -7.8 kcal/mol). Specific interactions in the agonist conformations involved arginine nitrogen with ASP-321 and GLU-323. Similarly, CYN displayed a preference for agonist conformations (1ERE: -6.7 kcal/mol; 3ERD: -7.0 kcal/mol) over antagonist conformations (1ERR: -6.6 kcal/mol; 3ERT: -6.1 kcal/mol). Key interactions in 1ERE involved the CYN guanidine group with SER-305, ALA-307, and ASP-369. In the case of AR, MC-LR showed a binding energy of -7.2 kcal/mol, with the leucine nitrogen interacting with PRO-682. CYN exhibited a higher affinity (-8.2 kcal/mol), with interactions involving the guanidine group with GLN-798. Taking this into account, computational docking analyses indicated possible binding interactions between these toxins and both receptors.

Acknowledgement: The authors would like to thank the MICIU/AEI/10.13039/501100011033 project; project number PID2019-104890RB-I00. A.C.-R. acknowledges the Spanish MICINN for the predoctoral grant awarded (PRE-2020-094412).