Acta Pharmacologica Sinica (2010) 31: 313–328; doi: 10.1038/aps.2009.193

Acta Pharmacologica Sinica (2010) 31: 313–328; doi: 10.1038/aps.2009.193; published online 8 February 2010

Original Article

Differential binding of bispyridinium oxime drugs with acetylcholinesterase

Manoj K KESHARWANI¹, Bishwajit GANGULY¹, Amit DAS², Tusar BANDYOPADHYAY^3,*

¹Analytical Science Discipline, Central Salt & Marine Chemicals Research Institute (Council of Scientific and Industrial Research), Bhavnagar, Gujarat, India 364 002; ²Protein Crystallography Section, Solid State Physics Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India 400 085; ³Theoretical Chemistry Section, Chemistry Group, Bhabha Atomic Research Centre, Trombay, Mumbai, India 400 085

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.

Keywords: acetylcholinesterase structure; nerve gas; oxime drugs; protein-drug complexes; steered molecular dynamics simulation

Financial support from DAE-BRNS, Mumbai, India is gratefully acknowledged (vide DAE-Sanction No 2007/37/19/BRNS). Manoj K KESHARWANI is thankful to UGC, New Delhi, India for the supporting fellowship. Tusar BANDYOPADHYAY is grateful to Prof T MUKHERJEE and Swapan K GHOSH for their constant encouragement during the course of the work. Manoj K KESHARWANI and Bishwajit GANGULY are thankful to Dr P K GHOSH for his support to this work.

* To whom correspondence should be addressed.
E-mail btusar@barc.gov.in
Received 2009-09-21 Accepted 2009-12-07

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