In silico analysis of the melamine structural analogues interaction with calcium-sensing receptor: A potential for nephrotoxicity

Abstract

• Study analysed binding profiles of common protein supplement adulterants to CaSR, known to mediate nephrotoxicity. • Melamine, cyanuric acid, melamine cyanurate, and uric acid favored CaSR's allosteric sites. • Melamine cyanurate exhibited the highest affinity. • These findings indicate an increased risk of nephrotoxicity when simultaneously exposed to melamine and cyanuric acid. • This study highlights the effectiveness of computational toxicology in elucidating clinical and in vivo findings. In recent years, melamine, and its structural analogues, as adulterants in various food products including protein supplements, have been widely studied for their nephrotoxic effects. Previous research has presented evidence that certain small molecules can alter the calcium-sensing receptor (CaSR) function, contributing to nephrotoxicity. Melamine, for example, has been observed in in vitro settings to interact with the allosteric binding site of CaSR, resulting in uncontrolled CaSR activation. This activation results in the production of reactive oxygen species, which eventually causes kidney cell apoptosis and/or necrosis. The present research used the in silico molecular modelling to evaluate the CaSR binding profiles of four common adulterants in protein supplements: melamine, cyanuric acid, uric acid, and melamine cyanurate. Using Schrödinger’s Maestro docking software (version 13.2.128), the docking studies coupled a noncovalent extra precision mode with the molecular mechanics-generalized born surface area (MM-GBSA) simulation for enhanced binding affinity prediction accuracy. This study identified that cyanuric acid, uric acid, and melamine cyanurate have greater CaSR binding affinities than melamine. Interestingly, melamine cyanurate had the highest binding potential to CaSR. Previous animal studies have reported high concentrations of melamine cyanurate complex in rat kidneys following melamine administration. These findings demonstrate a molecular explanation melamine cyanurate complex-induced nephrotoxicity. This research offers new insight regarding the probable mechanism through which melamine, its analogues, and complexes may cause nephrotoxicity.