PubMed · 15434983
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R HAZARD, A CORNEC, P PIGNARD. 1950. [Pseudocholinesterase and dihydroxycodeinone].. https://pubmed.ncbi.nlm.nih.gov/15434983/
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The synthesis of racemic and enantiomerically pure 3-butanamidoquinuclidines ((+/-)-Bu, (R)-Bu and (S)-Bu), (1-3) and 3-benzamidoquinuclidines ((+/-)-Bz, (R)-Bz, and (S)-Bz), (4-6) is described. The N-quaternary derivatives, N-benzyl-3-butanamidoquinuclidinium bromides ((+/-)-BnlBu, (R)-BnlBu and (S)-BnlBu), (7-9) and N-benzyl-3-benzamidoquinuclidinium bromides ((+/-)-BnlBz, (R)-BnlBz and (S)-BnlBz), (10-12) were subsequently synthesized. The interaction of the four enantiomerically pure quaternary derivatives with horse serum butyrylcholinesterase (BChE) was tested. All tested compounds inhibited the enzyme. The best inhibitior of the enzyme was (S)-BnlBz with a K(i) = 3.7 microM. The inhibitor potency decreases in order (S)-BnlBz > (R)-BnlBz >> (R)-BnlBu > (S)-BnlBu.
Molecular dynamics (MD) simulations and quantum mechanical/molecular mechanical (QM/MM) calculations were performed on the prereactive enzyme-substrate complex, transition states, intermediates, and product involved in the process of human butyrylcholinesterase (BChE)-catalyzed hydrolysis of (-)-cocaine. The computational results consistently reveal a unique role of the oxyanion hole (consisting of G116, G117, and A199) in BChE-catalyzed hydrolysis of cocaine, compared to acetylcholinesterase (AChE)-catalyzed hydrolysis of acetylcholine. During BChE-catalyzed hydrolysis of cocaine, only G117 has a hydrogen bond with the carbonyl oxygen (O31) of the cocaine benzoyl ester in the prereactive BChE-cocaine complex, and the NH groups of G117 and A199 are hydrogen-bonded with O31 of cocaine in all of the transition states and intermediates. Surprisingly, the NH hydrogen of G116 forms an unexpected hydrogen bond with the carboxyl group of E197 side chain and, therefore, is not available to form a hydrogen bond with O31 of cocaine in the acylation. The NH hydrogen of G116 is only partially available to form a weak hydrogen bond with O31 of cocaine in some structures involved in the deacylation. The change of the estimated hydrogen-bonding energy between the oxyanion hole and O31 of cocaine during the reaction process demonstrates how the protein environment can affect the energy barrier for each step of the BChE-catalyzed hydrolysis of cocaine. These insights concerning the effects of the oxyanion hole on the energy barriers provide valuable clues on how to rationally design BChE mutants with a higher catalytic activity for the hydrolysis of (-)-cocaine.
Slavins A (1) and B (2), the new amyrin type triterpenes, have been isolated from the chloroform soluble fraction of Salvia santolinifolia and assigned structures on the basis of spectral studies including 2D NMR. Both the compounds displayed inhibitory potential against the enzyme butyrylcholinesterase.