Understanding the Mechanism of Atovaquone Drug Resistance in Plasmodium falciparum Cytochrome b Mutation Y268S Using Computational Methods

Abstract

The rapid appearance of resistant malarial parasites after introduction of atovaquone (ATQ) drug has prompted the search for new drugs as even single point mutations in the active site of Cytochrome b protein can rapidly render ATQ ineffective. The presence of Y268 mutations in the Cytochrome b (Cyt b) protein is previously suggested to be responsible for the ATQ resistance in Plasmodium falciparum (P. falciparum). In this study, we examined the resistance mechanism against ATQ in P. falciparum through computational methods. Here, we reported a reliable protein model of Cyt bc1 complex containing Cyt b and the Iron-Sulphur Protein (ISP) of P. falciparum using composite modeling method by combining threading, ab initio modeling and atomic-level structure refinement approaches. The molecular dynamics simulations suggest that Y268S mutation causes ATQ resistance by reducing hydrophobic interactions between Cyt bc1 protein complex and ATQ. Moreover, the important histidine contact of ATQ with the ISP chain is also lost due to Y268S mutation. We noticed the induced mutation alters the arrangement of active site residues in a fashion that enforces ATQ to find its new stable binding site far away from the wild-type binding pocket. The MM-PBSA calculations also shows that the binding affinity of ATQ with Cyt bc1 complex is enough to hold it at this new site that ultimately leads to the ATQ resistance.

Quinoline-Based Hybrid Compounds with Antimalarial Activity

“…Resistance of plasmodium parasites to hydroxynaphthoquinones such as atovaquone is reported to be rapid and is due to a single-point mutation in the cytochrome-b gene [ 20 ]. Resistance of plasmodium parasites to diaminopyrimidine-based antimalarials such as pyrimethamine is due to the mutations in the gene for dihydrofolate reductase.…”

Decoding the Molecular Effects of Atovaquone Linked Resistant Mutations on Plasmodium falciparum Cytb-ISP Complex in the Phospholipid Bilayer Membrane

“…Once the ATQ drug binds at the Qo site, hydrophobic residue interactions are formed. The active site residues ( P. falciparum numbering) shown in Figure 2 D include: Met116, Ile119, Val120, Phe123, Val124, Met133, Trp136, Gly137, Val140, Ile141, Thr142, Leu144, Leu145, Ile155, Phe169, Leu172, Ile258, Val259, Pro260, Glu261, Trp262, Tyr263, Phe264, Phe267, Tyr268, Leu271, Val 284, Leu285 [ 18 ]. To facilitate the ET process, the metal cofactors such as the [2FE-2S] cluster are involved although they are located ~20 Å away from cytb subunit [ 19 , 20 ].…”

In silico study of subtilisin-like protease 1 (SUB1) from different Plasmodium species in complex with peptidyl-difluorostatones and characterization of potent pan-SUB1 inhibitors

“…Moreover, the same approach can be exploited for the development of new chemotherapeutics against P. vivax and P. knowlesi , which express orthologous SUB1 enzymes [11] . It is worth noticing that, differently from other drug targets in malaria in which rapid selection of mutants was observed (e.g., cytochrome b targeted by atovaquone [12] , [13] , [14] , [15] ), PfSUB1 represents a particularly excellent drug target because the likelihood of simultaneous compensatory mutations in both the protease active site and the substrate cleavage sites that might result in drug resistance is low. Endogenous substrates of PfSUB1 have been investigated and some studies analyzing in silico the interaction of peptides based on endogenous sequences with PfSUB1 and PvSUB1 have been previously in depth analyzed [6] , [11] , [16] , [17] , [18] .…”