In search of suitable protein targets for anti-malarial and anti-dengue drug discovery

A B S T R A C T Selecting suitable targets is the critical first step in drug discovery. However, for malaria and dengue this is quite a challenging step due to a large number of available structures for every disease targets, about 139 crystal structures for dengue and 367 structures for malaria. This study employed a combination of druggability filtering and computational analysis through molecular docking and molecular dynamics (MD) simulations in oder to select suitable drug targets for dengue and malaria. Initially, diverse target structures for dengue and malaria in Protein Data Bank were assessed for their druggability and as the result, druggable targets were chosen. There were three potential druggable targets NS5, NS3 and NS2BNS3 protease for dengue, and several targets involved in the food vacuole, apicoplast, mitochondria, cytosol, phosphatidylcholine synthesis pathways for malaria. Molecular docking of co-crystallised ligands with these targets was carried out and the complexes of targets satisfied with high binding affinies and RMSD values were selected. Subsequently, MD simulations of these complexes were run for 100 ns and different conformational structures of target proteins during the period of time were extracted for ensemble docking for each target. Re-docking results showed a significant difference in using equilibrium structures and initial structures from PDB. Finally, the suitable target structures were selected, including NS5 MTase for dengue and plasmepsin for malaria which can be used for further drug design studies.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

Selecting suitable drug targets is crucial in drug discovery. This study used a combination of druggability filtering, molecular docking, and molecular dynamics simulations to select suitable targets for dengue and malaria. The study identified druggable targets and performed molecular docking and MD simulations to evaluate their binding affinities. The results identified specific targets for further drug design studies.