Computational Biophysics of Drug-Target Interactions: In Silico Investigation of 2-Anilino-4-Amino Quinazoline Derivatives as Potential Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase Aurellyallodia Faiza Kusuma (a), Muhammad Farhan Shadiq (a), Rizarullah(b)(c), Reza Aditama (b), Sparisoma Viridi (b), Trina Tallei (d), Fifi Fitriyah Masduki (b*)
(a) Pradita Dirgantara High School, Boyolali
(b) Faculty of Mathematics and Natural Sciences, Bandung Institute of Technology
*f.masduki[at]itb.ac.id
(c) Department of Biochemistry, Faculty of Medicine, Abulyatama University, Aceh Besar
(d) Faculty of Mathematics and Natural Sciences,
Sam Ratulangi University, Manado
Abstract
abstract
Malaria, caused by Plasmodium parasites, is regarded as a major global health threat, further exacerbated by increasing resistance to current antimalarial drugs. Consequently, the urgent need for novel therapeutic agents is widely recognized. The 2-anilino-4-amino quinazoline scaffold has been identified as a promising candidate in antimalarial drug development. In this study, a series of substituted quinazoline derivatives were evaluated as potential inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a key enzyme involved in the parasite^s pyrimidine biosynthesis pathway. Molecular docking was carried out to investigate the binding modes and affinities of the compounds at the PfDHODH active site, with chloroquine being employed as a reference. Pharmacokinetic properties and drug-likeness were predicted using in silico ADMET analysis. The stability of the top ligand-PfDHODH complexes was subsequently examined through molecular dynamics simulations. Based on the computational results, favorable binding characteristics and pharmacokinetic profiles were exhibited by several quinazoline derivatives, indicating their potential as PfDHODH inhibitors. These findings are expected to provide a foundation for further structural optimization and experimental validation.
