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Virtual screening, docking, and dynamics of potential new inhibitors of dihydrofolate reductase from Yersinia pestis.

Author(s): Bastos Lda C, de Souza FR, Guimarães AP, Sirouspour M, Cuya Guizado TR, Forgione P, Ramalho TC, França TC

J Biomol Struct Dyn. 2016 Oct;34(10):2184-98 Authors: Bastos Lda C, de Souza FR, Guimarães AP, Sirouspour M, Cuya Guizado TR, Forgione P, Ramalho TC, França TC

Article GUID: 26494420
Docking and molecular dynamics studies of peripheral site ligand-oximes as reactivators of sarin-inhibited human acetylcholinesterase.

Author(s): de Almeida JS, Cuya Guizado TR, Guimarães AP, Ramalho TC, Gonçalves AS, de Koning MC, França TC

J Biomol Struct Dyn. 2016 Dec;34(12):2632-2642 Authors: de Almeida JS, Cuya Guizado TR, Guimarães AP, Ramalho TC, Gonçalves AS, de Koning MC, França TC

Article GUID: 26612005
Mechanistic studies of new oximes reactivators of human butyryl cholinesterase inhibited by cyclosarin and sarin.

Author(s): de Lima WE, Francisco A, da Cunha EF, Radic Z, Taylor P, França TC, Ramalho TC

J Biomol Struct Dyn. 2017 May;35(6):1272-1282 Authors: de Lima WE, Francisco A, da Cunha EF, Radic Z, Taylor P, França TC, Ramalho TC

Article GUID: 27125569
Title:Mechanistic studies of new oximes reactivators of human butyryl cholinesterase inhibited by cyclosarin and sarin.
Authors:de Lima WE,  Francisco A,  da Cunha EF,  Radic Z,  Taylor P,  França TC,  Ramalho TC
Link:https://www.ncbi.nlm.nih.gov/pubmed/27125569?dopt=Abstract
DOI:10.1080/07391102.2016.1178173
Category:J Biomol Struct Dyn
PMID:27125569
Dept Affiliation: CHEMISTRY
1 a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , MG 37200-000 , Brazil.
2 b Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California at San Diego , San Diego , CA , USA.
3 c Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense (LMCBD) , Military Institute of Engineering , Rio de Janeiro , RJ 22290-270 , Brazil.
4 d Department of Chemistry & Biochemistry , Concordia University , Montreal , QC , Canada.
5 e Faculty of Informatics and Management, Center for Basic and Applied Research , University of Hradec Kralove , Hradec Kralove , Czech Republic.

Description:

Mechanistic studies of new oximes reactivators of human butyryl cholinesterase inhibited by cyclosarin and sarin.

J Biomol Struct Dyn. 2017 May;35(6):1272-1282

Authors: de Lima WE, Francisco A, da Cunha EF, Radic Z, Taylor P, França TC, Ramalho TC

Abstract

Butyryl cholinesterase (BChE) has been seen as a key enzyme in the search for new strategies in the treatment of poisoning by organophosphates (OPs), since human BChE (HssBChE), complexed with the appropriate oxime, can be a suitable scavenger and deactivator for OPs in the blood stream. However, the efficacy of HssBChE is limited by its strict stoichiometric scavenging, slow reactivation, and propensity for aging. The improvement of the reactivation rate by new and more efficient oximes could contribute to mitigate this problem and increase the HssBChE efficiency as scavenger. Several oximes have been synthesized and tested with this goal, some with promising results, but the mechanistic aspects of the reactivation reaction are not fully understood yet. In order to better investigate this mechanism, docking and mixed quantum and molecular mechanics combined with principal components analysis were performed here to evaluate the capacity of reactivation and determine the preferred route for the reactivation reaction of two new oximes on HssBChE inhibited by the neurotoxic agents cyclosarin and sarin. Plots of potential energies were calculated and all the transition states of the reactional mechanism were determined. Our results showed a good correlation with experimental data and pointed to the most efficient oxime with both OPs. The protocol used could be a suitable tool for a preliminary evaluation of the HssBChE reactivation rates by new oximes.

PMID: 27125569 [PubMed - indexed for MEDLINE]