Quantum mechanics insights into melatonin and analogs binding to melatonin MT1 and MT2 receptors.

Melatonin receptors MT1 and MT2 are G protein-coupled receptors that mediate the effects of melatonin, a hormone involved in circadian rhythms and other physiological functions. Understanding the molecular interactions between these receptors and their ligands is crucial for developing novel therapeutic agents. In this study, we used molecular docking, molecular dynamics simulations, and quantum mechanics calculation to investigate the binding modes and affinities of three ligands: melatonin (MLT), ramelteon (RMT), and 2-phenylmelatonin (2-PMT) with both receptors. Based on the results, we identified key amino acids that contributed to the receptor-ligand interactions, such as Gln181/194, Phe179/192, and Asn162/175, which are conserved in both receptors. Additionally, we described new meaningful interactions with Gly108/Gly121, Val111/Val124, and Val191/Val204. Our results provide insights into receptor-ligand recognition's structural and energetic determinants and suggest potential strategies for designing more optimized molecules. This study enhances our understanding of receptor-ligand interactions and offers implications for future drug development.

Virtual screening of small natural compounds against NS1 protein of DENV, YFV and ZIKV.

Diseases caused by viruses of the genus Flavivirus are among the main diseases that affect the world and they are a serious public health problem. Three of them stand out: Dengue, Yellow fever and Zika viruses. The non-structural protein 1 (NS1), encoded by this viral genus, in its dimeric form, plays important roles in the pathogenesis and RNA replication of these viruses. Therefore, the identification of chemicals with the potential to inhibit the formation of the NS1 protein dimer of DENV, YFV and ZIKV would enable them to act as a multi-target drug. For this, we selected conformations of the NS1 protein monomer with similar ß-roll domain structure among the three virus species from conformations obtained from molecular dynamics simulations performed in GROMACS in 5 replicates of 150 ns for each species. After selecting the protein structures, a virtual screening of compounds from the natural products catalog of the ZINC database was performed using AutoDock Vina. The 100 best compounds were classified according efficiency criteria. Two compounds were observed in common to the species, with energy scores ranging from -9.2 kcal/mol to -10.1 kcal/mol. The results obtained here demonstrate the high similarity of NS1 proteins in the Flavivirus genus and high affinity for the same compounds; thus justifying the potential of these small molecules act in multitarget therapy.Communicated by Ramaswamy H. Sarma.