Abstract
In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity. Generally, mutations led to reduced binding affinity to pyrimethamine and increased conformational plasticity of DHFR. Next, dynamic residue network analysis (DRN) was applied to determine the impact of mutations and pyrimethamine binding on communication dispositions of DHFR residues. DRN revealed residues with distinctive communication profiles, distinguishing WT from drug-resistant mutants as well as pyrimethamine-bound from pyrimethamine-free models. Our results provide a new perspective on the understanding of mutation-induced drug resistance.
Highlights
Human malaria is a disease of global public health importance
Scientific reports highlighting the efficacy of the antimalarial drug combination, sulphadoxine pyrimethamine (SP), in intermittent preventive treatment during pregnancy (IPTp) and seasonal malaria chemoprevention (SMC) in children [4,5,6] led to the current WHO recommendations of its usage for IPTp and SMC in children
We focus on resistance to pyrimethamine which is mediated by non-synonymous mutations in the dihydrofolate reductase (DHFR) gene of P. falciparum [15]
Summary
Human malaria is a disease of global public health importance. Among the five causativePlasmodium species, Plasmodium falciparum is the most devastating [1]. Human malaria is a disease of global public health importance. Scientific reports highlighting the efficacy of the antimalarial drug combination, sulphadoxine pyrimethamine (SP), in intermittent preventive treatment during pregnancy (IPTp) and seasonal malaria chemoprevention (SMC) in children [4,5,6] led to the current WHO recommendations of its usage for IPTp and SMC in children. The pyrimethamine component of SP is an antifolate and a selective inhibitor of P. falciparum dihydrofolate reductase (Pf DHFR). Pf DHFR is among the best clinically validated and well-defined targets for antimalarial drug discovery [7]. It forms part of a dimeric assembly consisting of monomeric bifunctional units (Figure 1A,B). Each monomer is 608 residues long and is made up of a Molecules 2020, 25, 904; doi:10.3390/molecules25040904 www.mdpi.com/journal/molecules
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