TY - JOUR
T1 - Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators
AU - Pang, Yuan Ping
AU - Kollmeyer, Thomas M.
AU - Hong, Feng
AU - Lee, Jong Cheol
AU - Hammond, Pamela I.
AU - Haugabouk, Sharie P.
AU - Brimijoin, Stephen
N1 - Funding Information:
Support by the Mayo Foundation, the NIH (NS29646 to W.S.B.), the Defense Advanced Research Projects Agency (DAAD19-01-1-0322 to Y.-P.P.), the High Performance Computing Modernization Program of the DOD (allocations from ASC, AHPCRC, and ERDC to Y.-P.P.), and the University of Minnesota Supercomputing Institute (Y.-P.P.).
PY - 2003/6/1
Y1 - 2003/6/1
N2 - To improve the potency of 2-pralidoxime (2-PAM) for treating organophosphate poisoning, we dimerized 2-PAM and its analogs according to Wilson's pioneering work and the 3D structure of human acetylcholinesterase (hAChE) inactivated by isoflurophate. 1,7-Heptylene-bis-N,N'-syn-2-pyridiniumaldoxime, the most potent of the alkylene-linked dimeric reactivators, was readily synthesized using bistriflate and is 100 times more potent than 2-PAM in reactivating hAChE poisoned by isoflurophate. Experimental and computational studies confirm that 2-PAM in its biologically active form adopts the syn-I configuration. Further, they suggest that the improved performance of dimeric oximes is conferred by two-site binding with one oxime pointing toward the diisopropyl ester at the catalytic site of hAChE and the other anchored at the peripheral site. This type of binding may induce a conformational change in the acyl pocket loop which modulates the catalytic site via a domino effect.
AB - To improve the potency of 2-pralidoxime (2-PAM) for treating organophosphate poisoning, we dimerized 2-PAM and its analogs according to Wilson's pioneering work and the 3D structure of human acetylcholinesterase (hAChE) inactivated by isoflurophate. 1,7-Heptylene-bis-N,N'-syn-2-pyridiniumaldoxime, the most potent of the alkylene-linked dimeric reactivators, was readily synthesized using bistriflate and is 100 times more potent than 2-PAM in reactivating hAChE poisoned by isoflurophate. Experimental and computational studies confirm that 2-PAM in its biologically active form adopts the syn-I configuration. Further, they suggest that the improved performance of dimeric oximes is conferred by two-site binding with one oxime pointing toward the diisopropyl ester at the catalytic site of hAChE and the other anchored at the peripheral site. This type of binding may induce a conformational change in the acyl pocket loop which modulates the catalytic site via a domino effect.
UR - http://www.scopus.com/inward/record.url?scp=0037492336&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037492336&partnerID=8YFLogxK
U2 - 10.1016/S1074-5521(03)00126-1
DO - 10.1016/S1074-5521(03)00126-1
M3 - Article
C2 - 12837382
AN - SCOPUS:0037492336
SN - 1074-5521
VL - 10
SP - 491
EP - 502
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 6
ER -