Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Plasmodium falciparum Dihydroorotate Dehydrogenase, Fragment-based Drug Design, 2D-QSAR, DFT Calculation, Lead Optimization, Induced Fit Docking

Version 1 : Received: 17 December 2021 / Approved: 20 December 2021 / Online: 20 December 2021 (09:39:42 CET)

How to cite: Iwaloye, O.; Elekofehinti, O.; Olawale, F.; Chukwuemeka, P.; Babatomiwa, K.; Folorunso, I. Plasmodium falciparum Dihydroorotate Dehydrogenase, Fragment-based Drug Design, 2D-QSAR, DFT Calculation, Lead Optimization, Induced Fit Docking. Preprints 2021, 2021120296 (doi: 10.20944/preprints202112.0296.v1). Iwaloye, O.; Elekofehinti, O.; Olawale, F.; Chukwuemeka, P.; Babatomiwa, K.; Folorunso, I. Plasmodium falciparum Dihydroorotate Dehydrogenase, Fragment-based Drug Design, 2D-QSAR, DFT Calculation, Lead Optimization, Induced Fit Docking. Preprints 2021, 2021120296 (doi: 10.20944/preprints202112.0296.v1).

Abstract

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. This study sought to design new compounds from the fragments of known experimental inhibitors of PfDODH. Nine experimental compounds retrieved from Drug Bank online were downloaded and broken into fragments using Schrodinger power shell; the fragments were recombined to generate new ligand structures using 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 compounds electronic behaviours were studied using DFT calculations. Structural investigation of the six designed compounds, which had lower 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 attack. The current study thus provides insight into the development of a new set of potent PfDODH inhibitors.

Keywords

Plasmodium falciparum dihydroorotate dehydrogenase; fragment-based drug design; 2D-QSAR; DFT calculation; Lead optimization; Induced Fit docking

Subject

MEDICINE & PHARMACOLOGY, Pharmacology & Toxicology

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.