GENETIC AND IN SILICO STUDIES OF 6--PYRUVOYLTETRAHYDROPTERIN SYNTHASE IN Plasmodium falciparum ISOLATES

The lyase enzyme, 6-pyruvoyltetrahydropterin Synthase (6-PTPS) is involved in the biosynthesis of tetrahydrobiopterin. In Plasmodium species, where Dihydroneopterin Aldolase (DHNA) is absent, it acts in the synthesis of folate which is crucial for the optimum growth, development and survival of the parasite. This has been noted as a potential target for the development of antimalarial drugs. This study validated the presence of PfPTPS in P. falciparum-infected isolates, identified a relationship between parasite density and Cycle threshold and predicted compounds that could inhibit the enzyme and thereby serve as potential drugs against P. falciparum infection. Quantitative PCR was used to amplify the PfPTPS gene in isolates, and the resulting Cycle Threshold was compared with the parasite density. Molecular docking was done with PyRx to identify potential inhibitors of PfPTPS. The results show an inverse relationship between the parasite density and Cycle threshold. The first seven best hits ranked by the docking scores with better binding affinity than the control ligand, Biopterin were selected for visualisation, ADMET and toxicity studies. They include three conformers of the compound (I.D.140296439), and four other compounds (I.D. 140296495, 144380406, 135573878 and 136075207). In silico ADMET studies predicted good pharmacokinetic properties of the compounds and reported a high risk of irritant toxicity in 140296439 and 144380406. The study highlighted 140296439, 140296495, 144380406, 135573878 and 136075207 as potential inhibitors of PfPTPS and possible compounds for antimalarial drug development