Application of molecular docking and PSO–SVR intelligent approaches in antimalarial activity prediction of enantiomeric cycloguanil analogues

ABSTRACT

A series of antifolate compounds, i.e. 1-(4-chlorophenyl)-6,6-dimethyl-1,3,5-triazine-2,4-diamine, or cycloguanil analogues, have shown effective inhibiting properties against Plasmodium falciparum dihydrofolate reductase (PfDHFR). In this work, the stereoselectivity of PfDHFR to the R and S enantiomer of cycloguanil analogues was obtained from molecular docking calculations and integrated into QSAR study to obtain a more accurate prediction model. Results indicate that PfDHFR can bind to cycloguanil analogues in the R and S enantiomers. Cycloguanil analogues with alkyl chain substituent prefer the R enantiomer over S because they do not experience steric hindrance with the Phe58 side chain, while cycloguanil analogues with phenol chain substituent prefer the S enantiomer over R because they do not experience steric hindrance with Leu46 and Met55 side chains. Particle swarm optimization and support vector regression were used to select relevant descriptors and generate the effective prediction model, with a high statistical significance level (r²_training = 0.941; r²_test = 0.884).

KEYWORDS:

• QSAR
• cycloguanil analogues
• particle swarm optimization
• support vector regression
• molecular docking
• dihydrofolate reductase inhibitor
• stereochemistry

Supplemental data

Supplemental material for this article is available at: https://doi.org/10.1080/1062936X.2018.1536678

Acknowledgments

The authors gratefully acknowledge the financial support provided by Thammasat University Research Fund under the TU Research Scholar, contract no. 2/21/2559 and the Center of Excellence in Material Science, Construction, and Maintenance Technology Research Center. The authors would also like to thank the Center of Nanotechnology, Kasetsart University for the Gaussian 09 program package.

Disclosure statement

No potential conflict of interest was declared by the authors.

Additional information

Funding

This work was supported by the Center of Excellence in Material Science, Construction, and Maintenance Technology Research Center; Thammasat University Research Fund under the TU Research Scholar [contract no. 2/21/2559].