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Identification of Novel Molecular Targets of Four Microcystin Variants by High-Throughput Virtual Screening

Highly toxic microcystins (MCs) perform complex interactions with many proteins that induce cellular dysregulation, leading to the development of several diseases including cancer. There is significant diversity and chemical complexity among MC congeners, which makes it difficult to identify structure-dependent toxicity outcomes and their long-term effects. The aim of this study was to exploratory identify likely molecular targets of the main MC variants (MC-LA, MC-LR, MC-RR, and MC-LY) by conducting a computational binding affinity analysis using AutoDock Vina to evaluate the interaction of the toxins with 1000 proteins related to different biological functions. All four variants showed strong in silico interactions with proteins that regulate metabolism/immune system, CD38 (top scoring hit, −11.5 kcal/mol); inflammation, TLR4 (−11.4 kcal/mol) and TLR8 (−11.5 kcal/mol); neuronal conduction, BChE; renin–angiotensin signaling, (ACE); thyroid hormone homeostasis (TTR); and cancer-promoting processes, among other biochemical activities. The results show MCs have the potential to bind onto distinct molecular targets which could generate biochemical alterations through a number of signal transduction pathways. In short, this study broadens our knowledge about the mechanisms of action of different variants of microcystins and provides information for future direct experimentation.