Exploration of Quinolone Amides as Promising Candidates for the Treatment of Human African Trypanosomiasis: In Silico Virtual Screening and Molecular Docking

Abstract

Human african trypanosomiasis (HAT), commonly referred to as sleeping sickness, is a disease that originates from protozoan parasites of the Trypanosoma genus, which might be fatal if left untreated, or treated inadequately. Tsetse fly, a tropical blood-feeding insect, is generally the biological vector for this disease. Initially, the disease was neglected, however, when faced with the exploding number of cases, the urgent human needs for safe and cost-effective drugs combating the disease have increased significantly. The current study aims to computationally help advance the clinical care of HAT disease by leveraging computational tools to analyze the potential of quinolone amide derivatives to inhibit the enzyme responsible for this disease. The results demonstrate that jointly considering molecular affinity, polarity, and volume enables accurate inference of the bioactivity of quinolone derivatives, facilitating the efficient screening of large compound libraries. An effective QSAR model was developed using a dataset of 31 molecules, allowing reliable prediction of antitrypanosomal activity. Three promising compounds were identified based on their favorable physicochemical and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiles, as well as their strong binding interactions with ornithine decarboxylase (ODC) complexed with putrescine (PDB: 1F3T). Finally, a straightforward synthetic route was proposed for a novel compound with high biological potential. Overall, the study shows that an in-silico study can be used to efficiently drive a Quinolone-based drug design to target the HAT disease.