Multi-Targeted Design and Development of Dihydroisoquinolines as Potent Antimalarials

(E-pub Ahead of Print)

Author(s): Raviraj V. Mule*, Sneha P. Rochlani, Prafulla B. Choudhari, Rakesh P Dhavale, Manish S. Bhatia.

Journal Name: Current Computer-Aided Drug Design

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Background: Cysteine protease and DHODH enzyme were identified as potential target and for synthesized compound which revealed binding interaction and confirmation from docking study. Development of new lead which specifically targeting cysteine protease and DHODH enzyme can be able to reduce the side effect and to overcome multidrug resistance.

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

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

Result: A novel series of dihydroisoquinolines were designed by structure based drug design. Large compounds of dataset were screened for molecular docking study and subsequently all molecules were screened for drug like properties and toxicity study prior to synthesis. The designed molecules which analysed by virtual screening were synthesized, characterized and finally screened for antimalarial activity by performing bioassay. Synthesized compounds were showed greater antimalarial activity in terms percent inhibition.

Conclusion: In this work, compound A1,A5,A6,A9 showed desirable inhibitory activity toward targets in terms of percentage and also specific hydrogen binding interaction with those targets. Further optimization in leads able to yield drug like candidate and it may able to overcome multidrug resistance.

Keywords: Cysteine protease, Structure based drug design(SBDD), DHODH, Ligands, Molecular docking

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(E-pub Ahead of Print)
DOI: 10.2174/1573409915666191017145833
Price: $95

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