Structural perturbation of a dipalmitoylphosphatidylcholine (DPPC) bilayer by warfarin and its bolaamphiphilic analogue: A molecular dynamics study

Abstract

Compounds with nominally similar biological activity may exhibit differential toxicity due to differences in their interactions with cell membranes. Many pharmaceutical compounds are amphiphilic and can be taken up by phospholipid bilayers, interacting strongly with the lipid-aqueous interface whether or not subsequent permeation through the bilayer is possible. Bolaamphiphilic compounds, which possess two hydrophilic ends and a hydrophobic linker, can likewise undergo spontaneous uptake by bilayers. While membrane-spanning bolaamphiphiles can stabilize membranes, small molecules with this characteristic have the potential to create membrane defects via disruption of bilayer structure and dynamics. When compared to the amphiphilic therapeutic anticoagulant, warfarin, the bolaamphiphilic analogue, brodifacoum, exhibits heightened toxicity that goes beyond superior inhibition of the pharmacological target enzyme. We explore, herein, the consequences of anticoagulant accumulation in a dipalmitoylphosphatidylcholine (DPPC) bilayer. Coarse-grained molecular dynamics simulations reveal that permeation of phospholipid bilayers by brodifacoum causes a disruption of membrane barrier function that is driven by the bolaamphiphilic nature and size of this molecule. We find that brodifacoum partitioning into bilayers causes membrane thinning and permeabilization and promotes lipid flip-flop – phenomena that are suspected to play a role in triggering cell death. These phenomena are either absent or less pronounced in the case of the less toxic, amphiphilic compound, warfarin.

The relative toxicity of brodifacoum enantiomers

“…Likewise, BDF-poisoned bobcats (Lynx rufus) residing in southern California die predominantly from severe systemic inflammation elicited by parasite mites whereas BDF-poisoned mountain lions (Puma concolor) in the same area die from massive internal bleeding (Fraser et al, 2018;Serieys et al, 2018). In addition, we found that exposure of primary neuronal cells to BDF induced mitochondrial dysfunction and cell death (Marangoni et al, 2016) and that BDF (and other superwarfarins but not warfarin) can intercalate into and disrupt cell membranes (Ayee et al, 2016), which could dysregulate cell function and induce cell death. Although the mechanism(s) underlying these disparate toxic effects are uncertain, the presence of distinct BDF isomers in racemic BDF may play a role.…”

Microscopic view of lipids and their diverse biological functions

“…2) [50]. Another CG study found that membrane partitioning of toxic anticoagulant brodifacoum causes bilayer thinning and permeabilization that promotes lipid flip-flop, which potentially plays a role in triggering cell death [51]. In addition, atomistic umbrella sampling simulations on the flip-flop of PS showed that membrane oxidation decreases the energy barrier for translocation [52].…”

The emerging threat of superwarfarins: history, detection, mechanisms, and countermeasures

“…The second approach is to use coarse‐grained molecular dynamic simulations of BDF . While BDF is a highly lipophilic compound, its molecular structure possesses regions of polarity, such as the 4‐hydroxycoumarin moiety that BDF shares with warfarin.…”

“…The second approach is to use coarse-grained molecular dynamic simulations of BDF. 69 While BDF is a highly lipophilic compound, its molecular structure possesses regions of polarity, such as the 4-hydroxycoumarin moiety that BDF shares with warfarin. The compound is also a weak acid (pKa 5) and would be expected to adopt a predominately deprotonated, anionic form at physiological pH.…”