Asymmetric biodegradation of the nerve agents Sarin and VX by human dUTPase: chemometrics, molecular docking and hybrid QM/MM calculations

Abstract

OP nerve agents are among the most toxic chemical substances known. Their toxicity is due to their ability to bind to Acetylcholinesterase (AChE). Currently, some enzymes, such as Phosphotriesterase (PTE), Human Serum Paraoxonase 1 (HuPON1) and Diisopropyl Fluorophosphatase (DFPase), capable of degrading OP, have been characterized. Regarding the importance of bioremediation methods for detoxication of OP, this work aims to study the interaction modes between the human Human Deoxyuridine Triphosphate Nucleotidohydrolase (dUTPase) and Sarin and VX, considering their R and S enantiomers, to evaluate the asymmetric catalysis of those compounds. In previous work, this enzyme has shown good potential to degrade phosphotriesters, and based on this characteristic, we have applied the human dUTPase to the OP degradation. Molecular docking, chemometrics and QM/MM calculations have been employed, showing a good interaction between dUTPase and OP. Two possible reaction mechanisms were tested, and according to our theoretical results, the catalytic degradation of OP by dUTPase can take place via both mechanisms, beyond being stereoselective, i.e., dUTPase cleaves one enantiomer preferentially in relation to other. Chemometric techniques provided excellent assistance for the performing of this theoretical investigation. The dUTPase study shows importance by the fact of it being a human enzyme.

Organophosphorus Nerve Agents: Types, Toxicity, and Treatments

“…It consists of three active sites and requires divalent Mg 2+ for its activity. It is a potent enzyme and has shown to have a stereoselective preference toward P(−) enantiomer of VX [ 126 ]. Table 1 contains the list of variants of these organophosphatase and their compared activity with their respective wild types.…”

Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)

“…Some highly lipophilic OPs deposit in adipose tissues and are gradually released over several days after exposure. Some works have been performed to employ the enzymatic biodegradation of these compounds by using different degrading enzymes [34][35][36][37][38][39][40]. Along with OP, the carbamates (Figure 4) stand for the major class of insecticides involved in poisoning.…”

Novichok Nerve Agents as Inhibitors of Acetylcholinesterase—In Silico Study of Their Non-Covalent Binding Affinity

“…There are reports on the analysis of these compounds using theoretical and spectroscopic methods [ 9 , 10 , 13 , 15 , 16 ], and scarce in vitro research [ 17 ], yet there is, to the best of our knowledge, no information about any extensive in silico examinations of Novichoks’ mechanism of action and their potential reactivators. In reactivating the enzyme from OPNAs, several oxime-based compounds [ 18 , 19 , 20 , 21 , 22 ] as well as several engineered OPNA-degrading enzymes [ 14 ] are effective, and purely theoretical studies were conducted (e.g., [ 23 , 24 ]). Regarding Novichoks however, there is a lack of both QM and molecular mechanics (MM) investigations of Novichok–AChE interactions, including the noncovalent ones; yet, obviously, the noncovalent interplay between the ligand and the enzyme contributes to and facilitates the irreversible phosphonylation of the AChE catalytic-triad serine e.g., by adjusting the ligand electron density distribution therefore stabilizing the ligand in the enzyme active centre gorge and making it thus more susceptible to nucleophilic enzyme attack.…”