Virtual screening and molecular dynamics studies of novel small molecules targeting DHODH: identification of potential inhibitors.

Unlabelled: Schistosomiasis affects more than 200 million individuals globally, mainly in underprivileged areas, leading to long-term health issues and adding to socio-economic challenges. The existing reliance on a solitary medication (Praziquantel) gives rise to concerns about drug resistance and possible side effects. The exploration of alternative treatments is crucial to meet the demand for more efficient, safer, and cost-effective remedies, guaranteeing continuous control and eradication initiatives while reducing the risk of drug resistance. To address these issues, we employed a structure-based drug design approach, generating eighteen innovative inhibitors targeting Dihydroorotate dehydrogenase (SmDHODH). A robust QSAR model yielded promising statistical parameters, and molecular docking of 31 known inhibitors lead to the identification of a lead candidate (Compound ) with favorable binding efficacy. Eighteen novel compounds were designed, showing improved binding affinities compared to both the lead compound and the standard drug, Praziquantel (PZQ). Molecular dynamics simulations and Density Functional Theory (DFT) affirmed the reactivity and stability of protein-ligand complexes under physiological conditions. These compounds exhibit strong inhibition of SmDHODH and meet drug-likeness criteria. Additionally, they demonstrate favorable pharmacokinetic properties, suggesting their potential effectiveness in treating schistosomiasis. Our study underscores the importance of understanding molecular properties for optimizing treatments against this neglected tropical disease.

Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00281-6.