A search for FDA approved drugs with multiple antiemetic targets: A computational-based drug repositioning study

Emesis is a complex physiological response posing significant challenges in managing medical conditions such as gastroparesis, chemotherapy-induced nausea and vomiting (CINV), and post-operative nausea and vomiting (PONV). Antiemetic drugs are readily available; however, poor responses and adverse effects are still common, leading to non-compliance and exacerbation of existing health problems, thus underscoring the need for improved and innovative treatment strategies. This study aims to evaluate the potential of some selected FDA-approved drugs as multi-target antiemetic agents by assessing their binding affinities against key receptors involved in nausea and vomiting. D2, H1, and NK1 receptors using computational-based drug repositioning models. The 3D structures of human D2, H1, and NK1 receptors were obtained from the Protein Data Bank and known ligands of these targets with antiemetic effects were used to create a database of 33 drugs from the Drug Bank using a similarity search with a similarity threshold of 30%. Molecular docking simulations were performed using PyRx software to assess the binding affinities of the 33 drugs against the three receptors and the pharmacophores of the top 5 drugs were created using ligand-based pharmacophore modelling in LigandScout. Vancomycin, Dihydroergotamine, Dolutegravir, and Reserpine showed significant affinities across all three receptors. These drugs with their diverse pharmacological backgrounds showed promising results in addressing the complexity of emetic responses. The ligand-based pharmacophore modelling further emphasized the distinct characteristics of these drugs, and the most common pharmacophore feature shared among these compounds is the hydrogen bond acceptor. This study identifies the potential of Vancomycin , Dihydroergotamine, Dolutegravir, and Reserpine in addressing emesis through multi-receptor modulation. This warrants exploration in experimental settings, which will pave the way for innovative antiemetic therapies and improved patient outcomes by providing a basis for further research.