Virtual Screening of Natural Products and Drugs as Inhibitors against Aspartate Transcarbamoylase and Orotidine-5'-Monophosphate Decarboxylase inP lasmodium falciparum

Abstract

Background: Malaria remains to be one of the major health problems in tropical areas of the world. It puts at least one-third of the world population at risk of infection, and afflicts over 200 million people worldwide, approximately 7000 of which are Filipinos. In spite of available drugs, malarial chemotherapy is still insufficient. The rise of resistance of Plasmodium falciparum strains to existing antimalarial drugs prompts the discovery of new therapeutic agents for malaria.

Objective: This study is aimed to uncover, through molecular docking technique, new chemical entities that can be developed as new drugs for malaria.

Methodology: In this study, 2527 approved and 5755 experimental drugs from DrugBank and 4687 natural compounds from Analyticon MEGx database were docked against Plasmodium falciparum aspartate transcarbamoylase (PfATC) and oritidine-5'-monophosphate decarboxylase (PfOMPDC), two key enzyme targets involved in the de novo biosynthesis pathway of the pathogen.

Results: A total of 39 compounds (1 approved drug, 19 experimental drugs, 19 natural products) have larger binding energy (BE) values than the known ligands 2,3-naphthalenediol (BE = -7.0 kcal/mol) and uridine 5- PfATC monophosphate (BE = -9.0 kcal/mol). The top 3 hits were natural products: dihydrotrichotetronine (BE PfOMPDC PfATC = -21 kcal/mol, BE = -18 kcal/mol) , ginkgolide A (BE = -19 kcal/mol, BE = -15 kcal/mol), and PfOMPDC PfATC PfOMPDC ginkgolide C (BE = -16 kcal/mol, BE = -16 kcal/mol). PfATC PfOMPDC

Conclusion: Based on calculated binding energy and ADMET properties, dihydrotrichotetronine, ginkgolide A, and ginkgolide C are the best natural product candidates for further development as dual inhibitors for both PfATC and PfOMPDC enzymes. Furthermore, myricetin (BE = -9 kcal/mol, BE = -10 kcal/mol) and PfATC PfOMPDC tolcapone (BE = -9.1 kcal/mol, BE = -9.2 kcal/mol) may also be repurposed as anti-malarial drugs.