Title:Fragment-Based Drug Design, 2D-QSAR and DFT Calculation: Scaffolds
of 1, 2, 4, triazolo [1, 5-a] pyrimidin-7-amines as Potential Inhibitors of
Plasmodium falciparum Dihydroorotate Dehydrogenase
Volume: 20
Issue: 3
Author(s): Opeyemi Iwaloye*, Olusola Olalekan Elekofehinti, Femi Olawale, Prosper Obed Chukwuemeka, Babatomiwa Kikiowo and Ibukun Mary Folorunso
Affiliation:
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure,
Ondo State, P.M.B. 704, Akure, 360001 Nigeria
Keywords:
Plasmodium falciparum dihydroorotate dehydrogenase, fragment-based drug design, 2D-QSAR, DFT calculation, Lead optimization, induced fit docking.
Abstract:
Background: Plasmodium falciparum dihydroorotate dehydrogenase (PfDODH) is one of the
enzymes currently explored in the treatment of malaria. Although there is currently no clinically approved
drug targeting PfDODH, many of the compounds in clinical trials have [1, 2, 4,] triazolo [1, 5-a] pyrimidin-
7-amine backbone structure.
Objective: This study sought to design new compounds from the fragments of known experimental inhibitors
of PfDODH.
Methods: Nine experimental compounds retrieved from Drug Bank online were downloaded and broken
into fragments using the Schrodinger power shell; the fragments were recombined to generate new ligand
structures using the BREED algorithm. The new compounds were docked with PfDODH crystal structure,
after which the compounds were filtered with extensive drug-likeness and toxicity parameters. A
2D-QSAR model was built using the multiple linear regression method and externally validated. The
electronic properties of the compounds were calculated using the density functional theory method.
Results: Structural investigation of the six designed compounds, which had superior binding energies
than the standard inhibitors, showed that five of them had [1, 2, 4,] triazolo [1, 5-a] pyrimidin-7-amine
moieties and interacted with essential residues at the PfDODH binding site. In addition to their drug-like
and pharmacokinetic properties, they also showed minimal toxicities. The externally validated 2D-QSAR
model with R2 and Q2 values of 0.6852 and 0.6691 confirmed the inhibitory prowess of these compounds
against PfDODH. The DFT calculations showed regions of the molecules prone to electrophilic and nucleophilic
attacks.
Conclusion: The current study thus provides insight into the development of a new set of potent PfDODH
inhibitors.
