Binding free energy calculations to rationalize the interactions of huprines with acetylcholinesterase
In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters highlight the importance of the stereochemistry of huprines in AChE inhibition. Binding isotope effects are calculated to unravel the interactions between ligands and the gorge of AChE. New chemical insights are provided to explain and rationalize the experimental results. A good correlation with the experimental data is found for a family of inhibitors with moderate differences in the enzyme affinity. The analysis of the geometrical parameters and interaction energy per residue reveals that Asp72, Glu199, and His440 contribute significantly to the network of interactions between active site residues, which stabilize the inhibitors in the gorge. It seems that a cooperative effect of the residues of the gorge determines the affinity of the enzyme for these inhibitors, where Asp72, Glu199, and His440 make a prominent contribution.
KeywordsHuprines Binding free energy calculation QM/MM Stacking interactions Binding isotope effect
We thank Prof P. Camps, Prof. F.J. Luque, and Prof. D. Muñoz-Torrero for interesting comments on the paper. The authors acknowledge the financial support of the following agencies: Generalitat Valenciana for PrometeoII/2014/022, Ministerio de Economia y Competitividad, project CTQ2015-65207-P, Universitat Jaume I for project UJI-B2016-25. E.C.M. Nascimento is grateful to the Generalitat Valencia for Santiago Grisolia program 2011/040. We also wish to thank the Servei d’Informática, Universitat Jaume I, for the generous allocation of computer time.
Compliance with ethical standards
Conflict of interest
There are no conflicts of interest to declare.
- 3.Dunnett SB, Fibiger HC (1993) Role of forebrain cholinergic systems in learning and memory—relevance to the cognitive deficits of aging and alzheimer dementia. In: Cuello AC (ed) Cholinergic function and dysfunction, progress in brain research, vol 98. Elsevier Science Publ B V, Amsterdam, pp 413–420CrossRefGoogle Scholar
- 4.Weinstock M (1997) Possible role of the cholinergic system and disease models. J Neural Transm-Suppl 49:93–102Google Scholar
- 5.Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G (2012) Rang & Dale’s pharmacology, 7th edn. Elsevier, EdinburghGoogle Scholar
- 10.Gilson MK, Zhou HX (2007) Calculation of protein-ligand binding affinities. In: Annual review of biophysics and biomolecular structure, vol 36. Annual Reviews, Palo Alto, pp 21–42Google Scholar
- 14.Camps P, El Achab R, Görbig DM, Morral J, Muñoz-Torrero D, Badia A, Baños JE, Vivas NM, Barril X, Orozco M, Luque FJ (1999) Synthesis, in vitro pharmacology, and molecular modelling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of alzheimer’s disease. J Med Chem 42:3227–3242CrossRefGoogle Scholar
- 16.Camps P, El Achab R, Morral J, Muñoz-Torrero D, Badia A, Baños JE, Vivas NM, Barril X, Orozco M, Luque FJ (2000) New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of alzheimer’s disease. J Med Chem 43(24):4657–4666CrossRefGoogle Scholar
- 18.Barril X, Gelpi JL, Lopez JM, Orozco M, Luque FJ (2001) How accurate can molecular dynamics/linear response and Poisson-Boltzmann/solvent accessible surface calculations be for predicting relative binding affinities? acetylcholinesterase huprine inhibitors as a test case. Theor Chem Acc 106(1–2):2–9CrossRefGoogle Scholar
- 19.Dvir H, Wong DM, Harel M, Barril X, Orozco M, Luque FJ, Muñoz-Torrero D, Camps P, Rosenberry TL, Silman I, Sussman JL (2002) 3D structure of Torpedo californica acetylcholinesterase complexed with huprine X at 2.1 Å resolution: kinetic and molecular dynamic correlates. Biochemistry 41(9):2970–2981CrossRefGoogle Scholar
- 20.Camps P, Gomez E, Muñoz-Torrero D, Badia A, Clos MV, Curutchet C, Muñoz-Muriedas J, Luque FJ (2006) Binding of 13-amidohuprines to acetylcholinesterase: exploring the ligand-induced conformational change of the Gly117-Gly118 peptide bond in the oxyanion hole. J Med Chem 49(23):6833–6840CrossRefGoogle Scholar
- 21.Viayna E, Gomez T, Galdeano C, Ramirez L, Ratia M, Badia A, Clos MV, Verdaguer E, Junyent F, Camins A, Pallas M, Bartolini M, Mancini F, Andrisano V, Arce MP, Rodriguez-Franco MI, Bidon-Chanal A, Luque FJ, Camps P, Muñoz-Torrero D (2010) Novel huprine derivatives with inhibitory activity toward beta-amyloid aggregation and formation as disease-modifying anti-alzheimer drug candidates. ChemMedChem 5(11):1855–1870CrossRefGoogle Scholar
- 23.Camps P, Cusack B, Mallender WD, Achab RE, Morral J, Muñoz-Torrero D, Rosenberry TL (2000) Huprine X is a novel high-affinity inhibitor of acetylcholinesterase that is of interest for treatment of alzheimer’s disease. Mol Pharmacol 57(2):409–417Google Scholar
- 29.Wang L, Wu Y, Deng Y, Kim B, Pierce L, Krilov G, Lupyan D, Robinson S, Dahlgren MK, Greenwood J, Romero DL, Masse C, Knight JL, Steinbrecher T, Beuming T, Damm W, Harder E, Sherman W, Brewer M, Wester R, Murcko M, Frye L, Farid R, Lin T, Mobley DL, Jorgensen WL, Berne BJ, Friesner RA, Abel R (2015) Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field. J Am Chem Soc 137(7):2695–2703CrossRefGoogle Scholar
- 33.Field MJ (1999) A practical introduction to the simulation of molecular systems. Cambridge University Press, CambridgeGoogle Scholar