Differential binding of bispyridinium oxime drugs with acetylcholinesterase

Abstract

Aim: To performe a time-dependent topographical delineation of protein-drug interactions to gain molecular insight into the supremacy of Ortho-7 over HI-6 in reactivating tabun-conjugated mouse acetylcholinesterase (mAChE). Methods: We conducted all-atom steered molecular dynamics simulations of the two protein-drug complexes. Through a host of protein-drug interaction parameters (rupture force profiles, hydrogen bonds, water bridges, hydrophobic interactions), geometrical, and orientation ordering of the drugs, we monitored the enzyme's response during the release of the drugs from its active-site. Results: The results show the preferential binding of the drugs with the enzyme. The pyridinium ring of HI-6 shows excellent complementary binding with the peripheral anionic site, whereas one of two identical pyridinium rings of Ortho-7 has excellent binding compatibility in the enzyme active-site where it can orchestrate the reactivation process. We found that the active pyridinium ring of HI-6 undergoes a complete turn along the active site axis, directed away from the active-site region during the course of the simulation. Conclusion: Due to excellent cooperative binding of Ortho-7, as rendered by several cation-π interactions with the active-site gorge of the enzyme, Ortho-7 may be a more efficient reactivator than HI-6. Our work supports the growing body of evidence that the efficacy of the drugs is due to the differential bindings of the oximes with AChE and can aid to the rational design of oxime drugs.

Unbinding free energy of acetylcholinesterase bound oxime drugs along the gorge pathway from metadynamics-umbrella sampling investigation

“…The initial structures of the two AChE–oxime drug complexes were drawn from X‐ray crystallographic results using the PDB IDs: 2GYV (AChE–ortho‐7) and 2GYW (AChE–obidoxime). The PDB structures were repaired for missing residues and missing heavy atoms . Out of the dimeric structures of the complexes, only monomer A was chosen for modeling, since reportedly monomer A was better resolved in the electron density map.…”

“…Previous studies of bispyridinium oximes' binding to the mouse acetylcholinesterase (mAChE) gorge that addressed the issue of complementarities of the two pyridinium rings at the PAS and at the CAS region are based on steered MD (SMD) method. The SMD results revealed the participation of ligand–protein direct H‐bond (HB), hydrophobic interactions (HI), and water bridges (WB) during the whole process of oxime trafficking . These interactions either facilitate or hinder the passage along the pathway leading to free energy basins and barriers, as measured through the applications of nonequilibrium work theorems .…”

Energetics of Ortho-7 (Oxime Drug) Translocation through the Active-Site Gorge of Tabun Conjugated Acetylcholinesterase

“…The structure of the complex, mAChE-Tabun•Ortho-7 (PDB ID 2JF0) [10] was repaired for missing residues and missing heavy atoms [15]. Out of the dimeric X-ray crystal structure of the complex obtained at 2.5 Å resolution, only the monomer A chosen for modeling, since monomer A is better resolved in the electron density map.…”

Ortho‐7 bound to the active‐site gorge of free and OP‐conjugated acetylcholinesterase: Cation–π interactions

“…The dual binding ability makes the bispyridinium oxime drugs most potent reactivators against OP intoxication till today. Previous theoretical studies have focused on the involvement of various interactions, namely, drug–protein direct hydrogen bonding, hydrophobic interactions, and water bridges, prevailing in the AChE active‐site gorge, complexed with bispyridinium oxime drugs . Recent studies provide strong evidence that the bispyridinium oxime drugs form cation–π interactions with the aromatic residues both at the CAS and at the PAS .…”