Computational enzymology for degradation of chemical warfare agents: promising technologies for remediation processes

Abstract

Chemical weapons are a major worldwide problem, since they are inexpensive, easy to produce on a large scale and difficult to detect and control. Among the chemical warfare agents, we can highlight the organophosphorus compounds (OP), which contain the phosphorus element and that have a large number of applications. They affect the central nervous system and can lead to death, so there are a lot of works in order to design new effective antidotes for the intoxication caused by them. The standard treatment includes the use of an anticholinergic combined to a central nervous system depressor and an oxime. Oximes are compounds that reactivate Acetylcholinesterase (AChE), a regulatory enzyme responsible for the transmission of nerve impulses, which is one of the molecular targets most vulnerable to neurotoxic agents. Increasingly, enzymatic treatment becomes a promising alternative; therefore, other enzymes have been studied for the OP degradation function, such as phosphotriesterase (PTE) from bacteria, human serum paraoxonase 1 (HssPON1) and diisopropyl fluorophosphatase (DFPase) that showed significant performances in OP detoxification. The understanding of mechanisms by which enzymes act is of extreme importance for the projection of antidotes for warfare agents, and computational chemistry comes to aid and reduce the time and costs of the process. Molecular Docking, Molecular Dynamics and QM/MM (quantum-mechanics/molecular-mechanics) are techniques used to investigate the molecular interactions between ligands and proteins.

Keywords: computational methods; enzymatic biodegradation; oximes; warfare nerve agents.

Figure 1.. Basic structures of neurotoxic OP.

Figure 2.. HssAChE obtained from the PDB (Protein Data Bank). PDB ID: 3LII .

Figure 3.. Scheme of AChE inhibition and reactivation process.

Figure 4.. Chemical structures of pralidoxime, obidoxime, HI-6 and HLö-7.

Figure 5.. Crystallographic structure of PTE (PDB ID: 1DPM) .

Figure 6.. Proposed hydrolysis for OP (α/β = Zn²⁺) by PTE .

Figure 7.. Crystallographic structure of PON1 (PDB ID: 1V04) .

Figure 8.. Proposed reaction mechanisms for the hydrolysis of OP by HssPON1 and related mutants (M = Ca). Mechanisms (a) and (b) were described by Worek et al. , and mechanism (c) was described by Tawfik et al. .

Figure 9.. 3D structure of squid DFPase (PDB ID: 2GVV) .

Figure 10.. Proposed mechanisms for OP degradation by DFPase. (A) Through an activated water molecule by Asp229; (B) Through direct nucleophilic attack by Asp229 ,.