Quantitative Structure–Activity Relationships for Organophosphates Binding to Trypsin and Chymotrypsin

Abstract

Ruark, Christopher, D. M.S., Department of Pharmacology and Toxicology, Wright State University, 2010. Quantitative Structure-Activity Relationships for Organophosphates Binding to Trypsin and Chymotrypsin.Organophosphate (OP) nerve agents such as sarin, soman, tabun, and O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate (VX) do not react solely with acetylcholinesterase (AChE). Evidence suggests that a wide range of cholinergicindependent pathways are also targeted, including serine proteases. These proteases comprise nearly one-third of all known proteases and play major roles in synaptic plasticity, learning, memory, neuroprotection, wound healing, cell signaling, inflammation, blood coagulation and protein processing. Inhibition of these proteases by OPs was found to exert a wide range of noncholinergic effects depending on the type of OP, the dose, and the duration of exposure. Consequently, in order to understand these differences, in silico biologically-based dose-response and quantitative structure-activity relationship (QSAR) methodologies need to be integrated. Here, QSARs were used to predict OP bimolecular rate constants for trypsin and α-chymotrypsin. A heuristic regression of over 500 topological/constitutional, geometric, thermodynamic, electrostatic, and quantum mechanical descriptors, using the software Ampac 8.0 and Codessa 2.51 (SemiChem, Inc., Shawnee, KS), was developed to obtain statistically verified equations for the models. General models, using all data subsets, resulted in R

PON1 status does not influence cholinesterase activity in Egyptian agricultural workers exposed to chlorpyrifos

“…This provided the opportunity to test the hypothesis that repeated CPF exposures modify PON1 activity. There is significant experimental evidence that OPs can alter the activity of diverse enzymes (Casida and Quistad, 2005; Grigoryan et al , 2009; Lockridge and Schopfer, 2010; Ruark et al , 2011), so it is not inconceivable that either CPF or its oxon metabolite might alter the structure or function of PON1 or induce PON1 activity as a compensatory mechanism. If repeated CPF exposure altered PON1 activity, this might suggest not only an explanation of the discrepant findings between the Hofmann et al (2009) and Albers et al (2010) studies, but if PON1 activity were upregulated by repeated CPF exposure, it would suggest a compensatory mechanism to explain our earlier observation that Egyptian agricultural workers with repeated high exposures to CPF and greatly inhibited AChE nevertheless show no overt signs of toxicity (Farahat et al, 2011).…”

Molecular features and toxicological properties of four common pesticides, acetamiprid, deltamethrin, chlorpyriphos and fipronil

“…Nevertheless, QSAR studies involving quantum chemistry descriptors have been published for organophosphate binding to chymotrypsin and trypsin, the case of CHL being considered, but this study was limited to the semi-empirical level. 47 Four dihedral angles of chlorpyriphos (CHL, Figure 1) have been explored starting from the crystal structure (CPYRIF) 48 Table 3 together with the ones of the experimental structure observed in the crystalline state.…”

Indigenous Peoples of North America: Environmental Exposures and Reproductive Justice

“…The rendered oils of bowhead whale, seals, and walrus contain PCB concentrations of 193–421 ppb (Welfinger-Smith et al 2011). For reference, the U.S. EPA risk-based consumption limit for PCBs in fish to avoid excess risk of cancer is 1.5 ppb (Welfinger-Smith et al 2011). Rendered oils, blubber, and other fatty tissues from marine mammals are critical components of the traditional diet that provide important nutritional and cultural benefits.…”