Docking-Guided 3D-QSAR Studies of 4-Aminoquinoline-1,3,5-triazines as Inhibitors for  Plasmodium falciparum  Dihydrofolate Reductase

Radite Yogaswara; Maria Ludya Pulung; Sri Hartati Yuliani; Enade Perdana Istyastono

doi:10.22146/ijc.50674

Docking-Guided 3D-QSAR Studies of 4-Aminoquinoline-1,3,5-triazines as Inhibitors for Plasmodium falciparum Dihydrofolate Reductase

https://doi.org/10.22146/ijc.50674

Radite Yogaswara⁽¹⁾, Maria Ludya Pulung⁽²⁾, Sri Hartati Yuliani⁽³⁾, Enade Perdana Istyastono^(4*)

(1) Department of Chemistry Education, Faculty of Education and Teachers Training, University of Papua, Manokwari 98311, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Science, University of Papua, Manokwari 98311, Indonesia
(3) Faculty of Pharmacy, Sanata Dharma University, Paingan, Maguwoharjo, Depok, Sleman, Yogyakarta 55282, Indonesia
(4) Faculty of Pharmacy, Sanata Dharma University, Paingan, Maguwoharjo, Depok, Sleman, Yogyakarta 55282, Indonesia
(*) Corresponding Author

Abstract

Mutations in Plasmodium falciparum dihydrofolate reductase (PfDHFR), together with other mutations, hinder malaria elimination in Southeast Asia due to multiple drug resistance. In this article, molecular docking-guided three-dimensional (3D) quantitative structure-activity relationship (QSAR) analysis of 4-aminoquinoline-1,3,5-triazines as inhibitors for the wild-type (WT) PfDHFR to identify the molecular determinants of the inhibitors binding are presented. Compounds 4-aminoquinoline-1,3,5-triazines were reported promising to be developed as the non-resistant drugs. The 3D-QSAR analysis resulted in the best model with the R² and Q² values of 0.881 and 0.773, respectively. By correlating the molecular interaction fields (MIFs) of the best model to the docking pose employed to guide the 3D-QSAR analysis, S¹⁰⁸ residue of the WT-PfDHFR was unfortunately recognized as one of the molecular determinants. Since the S¹⁰⁸ residue is one of the mutation points of the PfDHFR mutants, the subsequent design strategy should modify the morpholine moiety to avoid the interaction with the S¹⁰⁸ residue of the WT-PfDHFR.

Keywords

Plasmodium falciparum dihydrofolate reductase; 3D-QSAR; molecular docking; multiple drug resistance

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DOI: https://doi.org/10.22146/ijc.50674