Abstract

Background: Malaria is a serious parasitic infection with greater morbidity and motility in recent decades. Cysteine protease and DHODH enzyme serve as a potential target for antimalarial agents which inhibit parasite multiplication in the erythrocyte stage. Development of new leads which specifically target cysteine protease and DHODH enzyme can reduce the side effects and overcome multidrug resistance.

Objectives: Representing the design and development of antimalarial agents by targeting cysteine protease and DHODH (Dihydroorotate dehydrogenase) enzyme by structure-based drug design.

Methods: In present work, the rational development of antimalarial agents by targeting cysteine protease and DHODH has been made by integrating binding confirmation from virtual analysis and synthetic procedures.

Results: A novel series of dihydroisoquinolines was designed by structure-based drug design. Compounds from the dataset were screened for interaction at the target site by performing molecular docking study and subsequently, all molecules were screened for drug-like properties and toxicity, prior to synthesis molecules subjected to virtual filters. Designed molecules which exceed these virtual filters were synthesized, characterized and finally screened for antimalarial activity.

Conclusion: In this work, it has been observed that compound A1, A5, A6 and A9 showed desirable biological activity towards targets and also specific hydrogen bonding interaction with the targets. Further optimization in leads yields a drug-like candidate and may overcome multidrug resistance.

Keywords: Structure-based drug design (SBDD), cysteine protease, DHODH, ligands, molecular docking, antimalarial activity.

Graphical Abstract