The deleterious effects of nerve agents over the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) turned these compounds into the most dangerous chemical weapons known. Among the antidotes in use today against these agents, oximes in combination with other drugs are the only treatment with any action. HI-6 and 2-PAM are cationic oximes proved to be effective for the reactivation of AChE inhibited by the nerve agents VX and sarin (GB). However, when it comes to reactivation of AChE inside the central or peripheral nervous systems, charged molecules present low diffusion due to low penetration through the blood-brain barrier. Uncharged oximes appear as an interesting alternative to solve this problem, but the development and enhancement of more efficient uncharged oximes capable of reactivating human AChE is still necessary. Given the limitations for in vivo and in vitro experimental studies with nerve agents, modeling is an important tool that can contribute to a better understanding of factors that may affect the efficiency of uncharged oximes. In order to investigate the interaction and behavior of cationic and uncharged oximes, we performed here molecular docking, molecular dynamics simulations, and binding energies calculations of the known cationic oximes HI-6 and 2-PAM plus four uncharged oximes found in the literature, complexed with human AChE (HssACHE) conjugated with the nerve agents VX and GB. The uncharged oximes showed different behaviors, especially RS194B, which presented stability inside AChE-VX, but presented free binding energy lower than cationic oximes, suggesting that structural alterations could favor its interactions with these complexes. In contrast, HI-6 and 2-PAM showed higher affinities with more negative binding energy values and larger contribution of the amino acid Asp74, demonstrating the importance of the quaternary nitrogen to the affinity and interaction of oximes with AChE-GB and AChE-VX conjugates.

Chemistry Institute Federal University of Rio de Janeiro 21941 901 Rio de Janeiro RJ Brazil

Department of Chemistry Faculty of Science University of Hradec Kralove Rokitanskeho 62 50003 Hradec Kralove Czech Republic

Department of Chemistry Pontifical Catholic University of Rio de Janeiro 22451 900 Rio de Janeiro RJ Brazil

Faculty of Technology University of the State of Rio de Janeiro 27537 000 Resende RJ Brazil

Laboratory of Molecular Modeling Applied to Chemical and Biological Defense Military Institute of Engineering 22290 270 Rio de Janeiro RJ Brazil

Postgraduate Program in Chemistry Federal University of Espírito Santo 29075 910 Vitória ESBrazil

Postgraduate Program in Sustainable Technologies Federal Institute of Education Science and Technology of Espírito Santo Unit Vila Velha 29056 255 Vila Velha ES Brazil

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Ribeiro T. S.; Prates A.; Alves S. R.; Oliveira-Silva J. J.; Riehl C. A. S.; Figueroa-Villar J. D. The Effect of Neutral Oximes on the Reactivation of Human Acetylcholinesterase Inhibited with Paraoxon. J. Braz. Chem. Soc. 2012, 23, 1216–1225. 10.1590/s0103-50532012000700004. DOI

Ganesan K.; Raza S.; Vijayaraghavan R. Chemical Warfare Agents. J. Pharm. Bioallied Sci. 2010, 2, 166–178. 10.4103/0975-7406.68498. PubMed DOI PMC

França T. C. C.; Silva G. R.; Castro A. T. Defesa Química: Uma Nova Disciplina No Ensino de Química. Rev. Virtual Química 2010, 2, 84–104.

Chauhan S.; Chauhan S.; D’Cruz R.; Faruqi S.; Singh K. K.; Varma S.; Singh M.; Karthik V. Chemical Warfare Agents. Environ. Toxicol. Pharmacol. 2008, 26, 113–122. 10.1016/j.etap.2008.03.003. PubMed DOI

Szinicz L. History of Chemical and Biological Warfare Agents. Toxicology 2005, 214, 167–181. 10.1016/j.tox.2005.06.011. PubMed DOI

Kim K.K.; Tsay O. G.; Atwood D. A.; Churchill D. G. Destruction and Detection of Chemical Warfare Agents. Chem. Rev. 2015, 111, 5345–403. 10.1021/cr100193y. PubMed DOI

Arias H. R.; Gu R.-X.; Feuerbach D.; Guo B.-B.; Ye Y.; Wei D.-Q. Novel Positive Allosteric Modulators of the Human Α7 Nicotinic Acetylcholine Receptor. Biochemistry 2011, 50, 5263–5278. 10.1021/bi102001m. PubMed DOI

Gu R.-X.; Zhong Y.-Q.; Wei D.-Q. Structural Basis of Agonist Selectivity for Different NAChR Subtypes: Insights from Crystal Structures, Mutation Experiments and Molecular Simulations. Curr. Pharm. Des. 2011, 17, 1652–1662. 10.2174/138161211796355119. PubMed DOI

Gonçalves A. d. S.; França T. C. C.; Figueroa-Villar J. D.; Pascutti P. G. Molecular Dynamics Simulations and QM/MM Studies of the Reactivation by 2-PAM of Tabun Inhibited Human Acethylcolinesterase. J. Braz. Chem. Soc. 2011, 22, 155–165. 10.1590/s0103-50532011000100021. DOI

Gonçalves A. d. S.; França T. C. C.; Wilter A.; Figueroa-Villar J. D. Molecular Dynamics of the Interaction of Pralidoxime and Deazapralidoxime with Acetylcholinesterase Inhibited by the Neurotoxic Agent Tabun. J. Braz. Chem. Soc. 2006, 17, 968–975. 10.1590/s0103-50532006000500022. DOI

Ajami D.; Rebek J. Chemical Approaches for Detection and Destruction of Nerve Agents. Org. Biomol. Chem. 2013, 11, 3936–4124. 10.1039/c3ob40324f. PubMed DOI

Larini L.Toxicologia Dos Praguicidas; Editora Manole: São Paulo, 1999.

Martin T.; Lobert S. Chemical Warfare. Toxicity of Nerve Agents. Crit. Care Nurse 2003, 23, 15–20. PubMed

Sidell F. R.; Takafuji E. T.; Franz D. R.. Medical Aspects of Chemical Warfare, 1a Edição.; United States Government Printing: Washington, 1997.

Marrs T. C.; Maynard R. L.; Sidell F. R. In Chemical Warfare Agents: Toxicology and Treatment, 2nd ed.; Marrs T. C., Maynard R. L., Sidell F. R., Eds.; John Wiley & Sons Ltd, 2007.

Bosgra S.; van Eijkeren J. C. H.; van der Schans M. J.; Langenberg J. P.; Slob W. Toxicodynamic Analysis of the Inhibition of Isolated Human Acetylcholinesterase by Combinations of Methamidophos and Methomyl in Vitro. Toxicol. Appl. Pharmacol. 2009, 236, 1–8. 10.1016/j.taap.2009.01.002. PubMed DOI

Bajgar J. Complex View on Poisoning with Nerve Agents and Organophosphates. Acta medica (Hradec Kral. 2005, 48, 3–21. 10.14712/18059694.2018.23. PubMed DOI

Delfino R. T.; Ribeiro T. S.; Figueroa-Villar J. D. Organophosphorus Compounds as Chemical Warfare Agents: A Review. J. Braz. Chem. Soc. 2009, 20, 407–428. 10.1590/s0103-50532009000300003. DOI

Karalliedde L.; Baker D.; Marrs T. C. Organophosphate-Induced Intermediate Syndrome. Toxicol. Rev. 2006, 25, 1–14. 10.2165/00139709-200625010-00001. PubMed DOI

Hulse E. J.; Davies J. O. J.; Simpson A. J.; Sciuto A. M.; Eddleston M. Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care. Am. J. Respir. Crit. Care Med. 2014, 190, 1342–1354. 10.1164/rccm.201406-1150ci. PubMed DOI PMC

Moretto A. Experimental and Clinical Toxicology of Anticholinesterase Agents. Toxicol. Lett. 1998, 102–103, 509–513. 10.1016/s0378-4274(98)00245-8. PubMed DOI

Mercey G.; Verdelet T.; Renou J.; Kliachyna M.; Baati R.; Nachon F.; Jean L.; Renard P.-Y. Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents. Acc. Chem. Res. 2012, 45, 756–766. 10.1021/ar2002864. PubMed DOI

Koplovitz I.; Stewart J. R. A Comparison of the Efficacy of HI6 and 2-PAM against Soman, Tabun, Sarin, and VX in the Rabbit. Toxicol. Lett. 1994, 70, 269–279. 10.1016/0378-4274(94)90121-x. PubMed DOI

Kuca K.; Jun D.; Musilek K. Structural Requirements of Acetylcholinesterase Reactivators. Mini Rev. Med. Chem. 2006, 6, 269–277. 10.2174/138955706776073510. PubMed DOI

Soukup O.; Tobin G.; Kumar U. K.; Binder J.; Proska J.; Jun D.; Fusek J.; Kuca K. Interaction of Nerve Agent Antidotes with Cholinergic Systems. Curr. Med. Chem. 2010, 17, 1708–1718. 10.2174/092986710791111260. PubMed DOI

Kuca K.; Musilek K.; Jun D.; Karasova J.; Soukup O.; Pejchal J.; Hrabinova M. Structure-Activity Relationship for the Reactivators of Acetylcholinesterase Inhibited by Nerve Agent VX. Med. Chem. 2013, 9, 689–693. 10.2174/1573406411309050008. PubMed DOI

Gonçalves A. d. S.; França T. C. C.; Caetano M. S.; Ramalho T. C. Reactivation Steps by 2-PAM of Tabun-Inhibited Human Acetylcholinesterase: Reducing the Computational Cost in Hybrid QM/MM Methods. J. Biomol. Struct. Dyn. 2014, 32, 301–307. 10.1080/07391102.2013.765361. PubMed DOI

Bester S. M.; Guelta M. A.; Cheung J.; Winemiller M. D.; Bae S. Y.; Myslinski J.; Pegan S. D.; Height J. J. Structural Insights of Stereospecific Inhibition of Human Acetylcholinesterase by VX and Subsequent Reactivation by HI-6. Chem. Res. Toxicol. 2018, 31, 1405–1417. 10.1021/acs.chemrestox.8b00294. PubMed DOI

Bajgar J.; Fusek J.; Kassa J.; Kuca K.; Jun D. Chemical Aspects of Pharmacological Prophylaxis against Nerve Agent Poisoning. Curr. Med. Chem. 2009, 16, 2977–2986. 10.2174/092986709788803088. PubMed DOI

Whitmore C.; Cook A. R.; Mann T.; Price M. E.; Emery E.; Roughley N.; Flint D.; Stubbs S.; Armstrong S. J.; Rice H.; et al. The Efficacy of HI-6 DMS in a Sustained Infusion against Percutaneous VX Poisoning in the Guinea-Pig. Toxicol. Lett. 2018, 293, 207–215. 10.1016/j.toxlet.2017.11.007. PubMed DOI

Reymond C.; Jaffré N.; Taudon N.; Menneteau M.; Chaussard H.; Denis J.; Castellarin C.; Dhote F.; Dorandeu F. Superior Efficacy of HI-6 Dimethanesulfonate over Pralidoxime Methylsulfate against Russian VX Poisoning in Cynomolgus Monkeys (Macaca Fascicularis). Toxicology 2018, 410, 96–105. 10.1016/j.tox.2018.09.005. PubMed DOI

Antonijevic B.; Stojiljkovic M. P. Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning. Clin. Med. Res. 2007, 5, 71–82. 10.3121/cmr.2007.701. PubMed DOI PMC

Kassa J.; Musilek K.; Zdarova Karasova J.; Kuca K.; Bajgar J. Two Possibilities How to Increase the Efficacy of Antidotal Treatment of Nerve Agent Poisonings. Mini Rev. Med. Chem. 2012, 12, 24–34. 10.2174/138955712798869011. PubMed DOI

Kuca K.; Cabal J.; Kassa J.; Jun D.; Hrabinová M. Comparison of in Vitro Potency of Oximes (Pralidoxime, Obidoxime, HI-6) to Reactivate Sarin-Inhibited Acetylcholinesterase in Various Parts of Pig Brain. J. Appl. Toxicol. 2005, 25, 271–276. 10.1002/jat.1053. PubMed DOI

Kuča K.; Musílek K.; Jun D.; Pohanka M.; Žd′árová Karasová J.; Novotný L.; Musilová L. Could Oxime HI-6 Really Be Considered as “Broad-Spectrum” Antidote?. J. Appl. Biomed. 2009, 7, 143–149. 10.32725/jab.2009.016. DOI

Radić Z.; Sit R. K.; Garcia E.; Zhang L.; Berend S.; Kovarik Z.; Amitai G.; Fokin V. V.; Sharpless K. B.; Taylor P. Mechanism of Interaction of Novel Uncharged, Centrally Active Reactivators with OP-HAChE Conjugates. Chem. Biol. Interact. 2013, 203, 67–71. 10.1016/j.cbi.2012.08.014. PubMed DOI PMC

Radić Z.; Sit R. K.; Kovarik Z.; Berend S.; Garcia E.; Zhang L.; Amitai G.; Green C.; Radić B.; Fokin V. V.; et al. Refinement of Structural Leads for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases. J. Biol. Chem. 2012, 287, 11798–11809. 10.1074/jbc.m111.333732. PubMed DOI PMC

Sit R. K.; Radić Z.; Gerardi V.; Zhang L.; Garcia E.; Katalinić M.; Amitai G.; Kovarik Z.; Fokin V. V.; Sharpless K. B.; et al. New Structural Scaffolds for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases. J. Biol. Chem. 2011, 286, 19422–19430. 10.1074/jbc.m111.230656. PubMed DOI PMC

Kovarik Z.; Maček N.; Sit R. K.; Radić Z.; Fokin V. V.; Barry Sharpless K.; Taylor P. Centrally Acting Oximes in Reactivation of Tabun-Phosphoramidated AChE. Chem. Biol. Interact. 2013, 203, 77–80. 10.1016/j.cbi.2012.08.019. PubMed DOI PMC

Tang M.; Wang Z.; Zhou Y.; Xu W.; Li S.; Wang L.; Wei D.; Qiao Z. A Novel Drug Candidate for Alzheimer’s Disease Treatment: Gx-50 Derived from Zanthoxylum Bungeanum. J. Alzheimer’s Dis. 2013, 34, 203–213. 10.3233/jad-121831. PubMed DOI

Szegezdi J.; Csizmadia F.. Prediction of Dissociation Constants Using Microconstants. In American Chemical Society National Meeting, 2004; pp 2–3.

Shao Y.; Molnar L. F.; Jung Y.; Kussmann J.; Ochsenfeld C.; Brown S. T.; Gilbert A. T. B.; Slipchenko L. V.; Levchenko S. V.; O’Neill D. P.; et al. Advances in Methods and Algorithms in a Modern Quantum Chemistry Program Package. Phys. Chem. Chem. Phys. 2006, 8, 3172–3191. 10.1039/b517914a. PubMed DOI

Rocha G. B.; Freire R. O.; Simas A. M.; Stewart J. J. P. RM1: A Reparameterization of AM1 for H, C, N, O, P, S, F, Cl, Br, and I. J. Comput. Chem. 2006, 27, 1101–1111. 10.1002/jcc.20425. PubMed DOI

Gonçalves A. d. S.; França T. C. C.; Figueroa-Villar J. D.; Pascutti P. G. Conformational Analysis of Toxogonine, TMB-4 and HI-6 Using PM6 and RM1 Methods. J. Braz. Chem. Soc. 2010, 21, 179–184. 10.1590/s0103-50532010000100025. DOI

de Souza F. R.; Garcia D. R.; Cuya T.; Kuca K.; Alencastro R. B.; França T. C. C. Behavior of Uncharged Oximes Compared to HI6 and 2-PAM in the Human AChE-Tabun Conjugate: A Molecular Modeling Approach. J. Biomol. Struct. Dyn. 2017, 36, 1430–1438. 10.1080/07391102.2017.1324322. PubMed DOI

de Souza F. R.; Guimarães A. P.; Cuya T.; Freitas M. P.; Gonçalves A. da S.; Forgione P.; Costa França T. C. Analysis of Coxiela Burnetti Dihydrofolate Reductase via in Silico Docking with Inhibitors and Molecular Dynamics Simulation. J. Biomol. Struct. Dyn. 2016, 35, 2975–2986. 10.1080/07391102.2016.1239550. PubMed DOI

Bastos L. d. C.; de Souza F. R.; Guimarães A. P.; Sirouspour M.; Guizado T. R. C.; Forgione P.; Ramalho T. C.; França T. C. C. Virtual Screening, Docking and Dynamics of Potential New Inhibitors of Dihydrofolate Reductase from Yersinia Pestis. J. Biomol. Struct. Dyn. 2015, 34, 2184–2198. 10.1080/07391102.2015.1110832. PubMed DOI

Berman H. M.; Westbrook J.; Feng Z.; Gilliland G.; Bhat T. N.; Weissig H.; Shindyalov I. N.; Bourne P. E. The Protein Data Bank. Nucleic Acids Res 2000, 28, 235–242. 10.1093/nar/28.1.235. PubMed DOI PMC

Ekström F.; Hörnberg A.; Artursson E.; Hammarström L. G.; Schneider G.; Pang Y. P. Structure of HI-6-Sarin-Acetylcholinesterase Determined by x-Ray Crystallography and Molecular Dynamics Simulation: Reactivator Mechanism and Design. PLoS One 2009, 4, e595710.1371/journal.pone.0005957. PubMed DOI PMC

Guex N.; Peitsch M. C. SWISS-MODEL and the Swiss-PdbViewer: An Environment for Comparative Protein Modeling. Electrophoresis 1997, 18, 2714–2723. 10.1002/elps.1150181505. PubMed DOI

Schwede T.; Kopp J.; Guex N.; Peitsch M. C. SWISS-MODEL: An Automated Protein Homology-Modeling Server. Nucleic Acids Res 2003, 31, 3381–3385. 10.1093/nar/gkg520. PubMed DOI PMC

Thomsen R.; Christensen M. H. MolDock : A New Technique for High-Accuracy Molecular Docking. J. Med. Chem. 2006, 49, 3315–3321. 10.1021/jm051197e. PubMed DOI

Pronk S.; Páll S.; Schulz R.; Larsson P.; Bjelkmar P.; Apostolov R.; Shirts M. R.; Smith J. C.; Kasson P. M.; Van Der Spoel D.; et al. GROMACS 4.5: A High-Throughput and Highly Parallel Open Source Molecular Simulation Toolkit. Bioinformatics 2013, 29, 845–854. 10.1093/bioinformatics/btt055. PubMed DOI PMC

Hess B.; Kutzner C.; Van Der Spoel D.; Lindahl E. GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. J. Chem. Theory Comput. 2008, 4, 435–447. 10.1021/ct700301q. PubMed DOI

Berendsen H. J. C.; Van der Spoel D.; Van Drunen R. GROMACS: A Message-Passing Parallel Molecular Dynamics Implementation. Comput. Phys. Commun. 1995, 91, 43–56. 10.1016/0010-4655(95)00042-e. DOI

Van Der Spoel D.; Lindahl E.; Hess B.; Groenhof G.; Mark A. E.; Berendsen H. J. C. GROMACS: Fast, Flexible, and Free. J. Comput. Chem. 2005, 26, 1701–1718. 10.1002/jcc.20291. PubMed DOI

Martínez L.; Borin I. A.; Skaf M. S.. Fundamentos de Simulação Por Dinâmica Molecular. In Métodos de Química Teórica e Modelagem Molecular; Morgon N. H., Coutinho K., Eds.; Editora Livraria da Física, 2007; pp 413–452.

Jorgensen W. L.; Chandrasekhar J.; Madura J. D.; Impey R. W.; Klein M. L. Comparison of Simple Potential Functions for Simulating Liquid Water. J. Chem. Phys. 1983, 79, 926–935. 10.1063/1.445869. DOI

Harrach M. F.; Drossel B. Structure and Dynamics of TIP3P, TIP4P, and TIP5P Water near Smooth and Atomistic Walls of Different Hydroaffinity. J. Chem. Phys. 2014, 140, 174501.10.1063/1.4872239. PubMed DOI

Mark P.; Nilsson L. Structure and Dynamics of the TIP3P, SPC, and SPC/E Water Models at 298 K. J. Phys. Chem. A 2001, 105, 9954–9960. 10.1021/jp003020w. DOI

Kaminski G. A.; Friesner R. A.; Tirado-rives J.; Jorgensen W. L. Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides. J. Phys. Chem. B 2001, 105, 6474–6487. 10.1021/jp003919d. DOI

Sousa da Silva A. W.; Vranken W. F. ACPYPE - AnteChamber PYthon Parser InterfacE. BMC Res. Notes 2012, 5, 367.10.1186/1756-0500-5-367. PubMed DOI PMC

Ribeiro A. A. S. T.; Horta B. A. C.; Alencastro R. B. d. MKTOP: A Program for Automatic Construction of Molecular Topologies. J. Braz. Chem. Soc. 2008, 19, 1433–1435. 10.1590/s0103-50532008000700031. DOI

Cornell W. D.; Cieplak P.; Bayly C. I.; Kollman P. a.; Kollmann P. A. Application of RESP Charges To Calculate Conformational Energies, Hydrogen Bond Energies, aCrgies of Solvation. J. Am. Chem. Soc. 1993, 115, 9620–9631. 10.1021/ja00074a030. DOI

Bayly C. I.; Cieplak P.; Cornell W.; Kollman P. a. A Well-Behaved Electrostatic Potential Based Method Using Charge Restraints for Deriving Atomic Charges: The RESP Model. J. Phys. Chem. 1993, 97, 10269–10280. 10.1021/j100142a004. DOI

Wang J.; Cieplak P.; Kollman P. A. How Well Does a Restrained Electrostatic Potential (RESP) Model Perform in Calculating Conformational Energies of Organic and Biological Molecules?. J. Comput. Chem. 2000, 21, 1049–1074. 10.1002/1096-987x(200009)21:12<1049::aid-jcc3>3.0.co;2-f. DOI

Jakalian A.; Jack D. B.; Bayly C. I. Fast, Efficient Generation of High-Quality Atomic Charges. AM1-BCC Model: II. Parameterization and Validation. J. Comput. Chem. 2002, 23, 1623–1641. 10.1002/jcc.10128. PubMed DOI

Gonewar N. R.; Jadhav V. B. J. K. D.; Sarawadekar R. G. Theoretical Calculations of Infrared, NMR and Electronic Spectra of 2-Nitroso-1, Naphthol or 1-2 Naphthoquinine-2 Oxime and Comparison with Experimental Data. Res. Pharm. 2012, 2, 18–25.

Byrd R. H.; Lu P.; Nocedal J.; Zhu C. A Limited Memory Algorithm for Bound Constrained Optimization. SIAM J. Sci. Comput. 1995, 16, 1190–1208. 10.1137/0916069. DOI

Bosko J. T.; Todd B. D.; Sadus R. J. Molecular Simulation of Dendrimers and Their Mixtures under Shear: Comparison of Isothermal-Isobaric (NpT) and Isothermal-Isochoric (NVT) Ensemble Systems. J. Chem. Phys. 2005, 123, 034905.10.1063/1.1946749. PubMed DOI

Evans D. J.; Holian B. L. The Nose-Hoover Thermostat. J. Chem. Phys. 1985, 83, 4069–4074. 10.1063/1.449071. DOI

Parrinello M.; Rahman A. Polymorphic Transitions in Single Crystals: A New Molecular Dynamics Method. J. Appl. Phys. 1981, 52, 7182–7190. 10.1063/1.328693. DOI

Humphrey W.; Dalke A.; Schulten K. VDM: Visual Molecular Dynamics. J. Mol. Graph. 1996, 14, 33–38. 10.1016/0263-7855(96)00018-5. PubMed DOI

de Almeida J. S. F. D.; Guizado T. R.; Guimaraes A. P.; Ramalho T. C.; Goncalves A. S.; de Koning M. C.; Franca T. C. Docking and Molecular Dynamics Studies of Peripheral Site Ligand-Oximes as Reactivators of Sarin-Inhibited Human Acetylcholinesterase. J. Biomol. Struct. Dyn. 2016, 34, 2632–2642. 10.1080/07391102.2015.1124807. PubMed DOI

Kar P.; Lipowsky R.; Knecht V. Importance of Polar Solvation and Configurational Entropy for Design of Antiretroviral Drugs Targeting HIV-1 Protease. J. Phys. Chem. B 2013, 117, 5793–5805. 10.1021/jp3085292. PubMed DOI

Jayaram B.; Sprous D.; Young M. A.; Beveridge D. L. Free Energy Analysis of the Conformational Preferences of A and B Forms of DNA in Solution. J. Am. Chem. Soc. 1998, 120, 10629–10633. 10.1021/ja981307p. DOI

Vorobjev Y. N.; Almagro J. C.; Hermans J. Discrimination between Native and Intentionally Misfolded Conformations of Proteins: ES/IS, a New Method for Calculating Conformational Free Energy That Uses Both Dynamics Simulations with an Explicit Solvent and an Implicit Solvent Continuum Model. Proteins Struct. Funct. Genet. 1998, 32, 399–413. 10.1002/(sici)1097-0134(19980901)32:4<399::aid-prot1>3.0.co;2-c. PubMed DOI

Estévez J.; Rodrigues de Souza F.; Romo M.; Mangas I.; Costa Franca T. C.; Vilanova E. Interactions of Human Butyrylcholinesterase with Phenylvalerate and Acetylthiocholine as Substrates and Inhibitors: Kinetic and Molecular Modeling Approaches. Arch. Toxicol. 2019, 93, 1281–1296. 10.1007/s00204-019-02423-8. PubMed DOI

Garcia D. R.; Souza F. R.; Paula Guimarães A.; Castro Ramalho T.; Palermo de Aguiar A.; Celmar Costa França T. Design of Inhibitors of Thymidylate Kinase from Variola Virus as New Selective Drugs against Smallpox: Part II. J. Biomol. Struct. Dyn. 2019, 37, 4569–4579. 10.1080/07391102.2018.1554510. PubMed DOI PMC

Kumari R.; Kumar R.; Lynn A. g_mmpbsa-A GROMACS Tool for High-Throughput MM-PBSA Calculations. J. Chem. Inf. Model. 2014, 54, 1951–1962. 10.1021/ci500020m. PubMed DOI

Homeyer N.; Gohlke H. Free Energy Calculations by the Molecular Mechanics Poisson-Boltzmann Surface Area Method. Mol. Inform. 2012, 31, 114–122. 10.1002/minf.201100135. PubMed DOI

Baker N. A.; Sept D.; Joseph S.; Holst M. J.; McCammon J. A. Electrostatics of Nanosystems: Application to Microtubules and the Ribosome. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 10037–10041. 10.1073/pnas.181342398. PubMed DOI PMC

Sitkoff D.; Sharp K. A.; Honig B. Accurate Calculation of Hydration Free Energies Using Macroscopic Solvent Models. J. Phys. Chem. 1994, 98, 1978–1988. 10.1021/j100058a043. DOI

Edwards P. M. Origin 7.0: Scientific Graphing and Data Analysis Software. J. Chem. Inf. Comput. Sci. 2002, 42, 1270–1271. 10.1021/ci0255432. DOI

Maiti R.; Van Domselaar G. H.; Zhang H.; Wishart D. S. SuperPose: A Simple Server for Sophisticated Structural Superposition. Nucleic Acids Res 2004, 32, 590–594. 10.1093/nar/gkh477. PubMed DOI PMC

Pettersen E. F.; Goddard T. D.; Huang C. C.; Couch G. S.; Greenblatt D. M.; Meng E. C.; Ferrin T. E. UCSF Chimera - A Visualization System for Exploratory Research and Analysis. J. Comput. Chem. 2004, 25, 1605–1612. 10.1002/jcc.20084. PubMed DOI

Pedregal J. R.-G.; Maréchal J.-D. PyChimera: use UCSF Chimera modules in any Python 2.7 project. Bioinformatics 2018, 34, 1784–1785. 10.1093/bioinformatics/bty021. PubMed DOI

Kuca K.; Cabal J.; Kassa J.; Jun D.; Hrabinova M. Vitro Potency of H Oximes (HI-6, HLö-7), the Oxime BI-6, and Currently Used Oximes (Pralidoxime, Obidoxime, Trimedoxime) to Reactivate Nerve Agent-Inhibited Rat Brain Acetylcholinesterase. J. Toxicol. Environ. Health. A 2006, 69, 1431–1440. 10.1080/15287390500364283. PubMed DOI

Olson C. T.; Menton R. G.; Riser R. C.; Matthews M. C.; Stotts R. R.; Romano J. R.; Koplovitz I.; Hackley B. E.; Johnson J. B. Efficacies of Atropine/2-PAM and Atropine/HI-6 in Treating Monkeys Intoxicated with Organophosphonate Nerve Agents. Int. J. Toxicol. 1997, 16, 9–20. 10.1080/109158197227314. DOI

Kassa J.; Jun D.; Kuca K. The Reactivating and Therapeutic Efficacy of Oximes to Counteract Russian VX Poisonings. Int. J. Toxicol. 2006, 25, 397–401. 10.1080/10915810600846971. PubMed DOI

Kuca K.; Jun D.; Cabal J.; Hrabinova M.; Bartosova L.; Opletalova V. Russian VX: Inhibition and Reactivation of Acetylcholinesterase Compared with VX Agent. Basic Clin. Pharmacol. Toxicol. 2006, 98, 389–394. 10.1111/j.1742-7843.2006.pto_267.x. PubMed DOI

Hörnberg A.; Tunemalm A.-K.; Ekström F. Crystal Structures of Acetylcholinesterase in Complex with Organophosphorus Compounds Suggest That the Acyl Pocket Modulates the Aging Reaction by Precluding the Formation of the Trigonal Bipyramidal Transition State. Biochemistry 2007, 46, 4815–4825. 10.1021/bi0621361. PubMed DOI

Millard C. B.; Koellner G.; Ordentlich A.; Shafferman A.; Silman I.; Sussman J. L. Reaction Products of Acetylcholinesterase and VX Reveal a Mobile Histidine in the Catalytic Triad. J. Am. Chem. Soc. 1999, 121, 9883–9884. 10.1021/ja992704i. DOI

Artursson E.; Andersson P. O.; Akfur C.; Linusson A.; Börjegren S.; Ekström F. Catalytic-Site Conformational Equilibrium in Nerve-Agent Adducts of Acetylcholinesterase: Possible Implications for the HI-6 Antidote Substrate Specificity. Biochem. Pharmacol. 2013, 85, 1389–1397. 10.1016/j.bcp.2013.01.016. PubMed DOI

Franjesevic A. J.; Sillart S. B.; Beck J. M.; Vyas S.; Callam C. S.; Hadad C. M. Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase. Chem.—A Eur. J. 2019, 25, 5337–5371. 10.1002/chem.201805075. PubMed DOI PMC

Mallender W. D.; Szegletes T.; Rosenberry T. L. Acetylthiocholine Binds to Asp74 at the Peripheral Site of Human Acetylcholinesterase as the First Step in the Catalytic Pathway. Biochemistry 2000, 39, 7753–7763. 10.1021/bi000210o. PubMed DOI

Johnson G.; Moore S. The Peripheral Anionic Site of Acetylcholinesterase: Structure, Functions and Potential Role in Rational Drug Design. Curr. Pharm. Des. 2006, 12, 217–225. 10.2174/138161206775193127. PubMed DOI

De Koning M. C.; Joosen M. J. A.; Noort D.; Van Zuylen A.; Tromp M. C. Peripheral Site Ligand-Oxime Conjugates: A Novel Concept towards Reactivation of Nerve Agent-Inhibited Human Acetylcholinesterase. Bioorganic Med. Chem. 2011, 19, 588–594. 10.1016/j.bmc.2010.10.059. PubMed DOI