Linusson A


Full name : Linusson Anna

First name : Anna

Mail : Umea University\; Chemistry\; Department of Chemistry\; Umea University\; SE-90187 Umea

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Country : Sweden

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References (16)

Title : Structure-Activity Relationships Reveal Beneficial Selectivity Profiles of Inhibitors Targeting Acetylcholinesterase of Disease-Transmitting Mosquitoes - Vidal-Albalat_2023_J.Med.Chem__
Author(s) : Vidal-Albalat A , Kindahl T , Rajeshwari R , Lindgren C , Forsgren N , Kitur S , Tengo LS , Ekstrom F , Kamau L , Linusson A
Ref : Journal of Medicinal Chemistry , : , 2023
Abstract : Insecticide resistance jeopardizes the prevention of infectious diseases such as malaria and dengue fever by vector control of disease-transmitting mosquitoes. Effective new insecticidal compounds with minimal adverse effects on humans and the environment are therefore urgently needed. Here, we explore noncovalent inhibitors of the well-validated insecticidal target acetylcholinesterase (AChE) based on a 4-thiazolidinone scaffold. The 4-thiazolidinones inhibit AChE1 from the mosquitoes Anopheles gambiae and Aedes aegypti at low micromolar concentrations. Their selectivity depends primarily on the substitution pattern of the phenyl ring; halogen substituents have complex effects. The compounds also feature a pendant aliphatic amine that was important for activity; little variation of this group is tolerated. Molecular docking studies suggested that the tight selectivity profiles of these compounds are due to competition between two binding sites. Three 4-thiazolidinones tested for in vivo insecticidal activity had similar effects on disease-transmitting mosquitoes despite a 10-fold difference in their in vitro activity.
ESTHER : Vidal-Albalat_2023_J.Med.Chem__
PubMedSearch : Vidal-Albalat_2023_J.Med.Chem__
PubMedID: 37094110

Title : Broad-spectrum antidote discovery by untangling the reactivation mechanism of nerve agent inhibited acetylcholinesterase - Lindgren_2022_Chemistry_28_e202200678
Author(s) : Lindgren C , Forsgren N , Hoster N , Akfur C , Artursson E , Edvinsson L , Svensson R , Worek F , Ekstrom , Linusson A
Ref : Chemistry , 28 :e202200678 , 2022
Abstract : Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and prereactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.
ESTHER : Lindgren_2022_Chemistry_28_e202200678
PubMedSearch : Lindgren_2022_Chemistry_28_e202200678
PubMedID: 35420233
Gene_locus related to this paper: mouse-ACHE

Title : Physical Mechanisms Governing Substituent Effects on Arene-Arene Interactions in a Protein Milieu - Andersson_2020_J.Phys.Chem.B_124_6529
Author(s) : Andersson CD , Mishra BK , Forsgren N , Ekstrom F , Linusson A
Ref : J Phys Chem B , 124 :6529 , 2020
Abstract : Arene-arene interactions play important roles in protein-ligand complex formation. Here, we investigate the characteristics of arene-arene interactions between small organic molecules and aromatic amino acids in protein interiors. The study is based on X-ray crystallographic data and quantum mechanical calculations using the enzyme acetylcholinesterase and selected inhibitory ligands as a model system. It is shown that the arene substituents of the inhibitors dictate the strength of the interaction and the geometry of the resulting complexes. Importantly, the calculated interaction energies correlate well with the measured inhibitor potency. Non-hydrogen substituents strengthened all interaction types in the protein milieu, in keeping with results for benzene dimer model systems. The interaction energies were dispersion-dominated, but substituents that induced local dipole moments increased the electrostatic contribution and thus yielded more strongly bound complexes. These findings provide fundamental insights into the physical mechanisms governing arene-arene interactions in the protein milieu and thus into molecular recognition between proteins and small molecules.
ESTHER : Andersson_2020_J.Phys.Chem.B_124_6529
PubMedSearch : Andersson_2020_J.Phys.Chem.B_124_6529
PubMedID: 32610016
Gene_locus related to this paper: mouse-ACHE

Title : Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency - Knutsson_2018_J.Med.Chem_61_10545
Author(s) : Knutsson S , Engdahl C , Kumari R , Forsgren N , Lindgren C , Kindahl T , Kitur S , Wachira L , Kamau L , Ekstrom F , Linusson A
Ref : Journal of Medicinal Chemistry , 61 :10545 , 2018
Abstract : Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure-activity relationship analyses and molecular dynamics simulations of inhibitor-protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.
ESTHER : Knutsson_2018_J.Med.Chem_61_10545
PubMedSearch : Knutsson_2018_J.Med.Chem_61_10545
PubMedID: 30339371
Gene_locus related to this paper: mouse-ACHE

Title : Influence of Enantiomeric Inhibitors on the Dynamics of Acetylcholinesterase Measured by Elastic Incoherent Neutron Scattering - Andersson_2018_J.Phys.Chem.B_122_8516
Author(s) : Andersson CD , Martinez N , Zeller D , Allgardsson A , Koza MM , Frick B , Ekstrom F , Peters J , Linusson A
Ref : J Phys Chem B , 122 :8516 , 2018
Abstract : The enzyme acetylcholinesterase (AChE) is essential in humans and animals because it catalyzes the breakdown of the nerve-signaling substance acetylcholine. Small molecules that inhibit the function of AChE are important for their use as drugs in the, for example, symptomatic treatment of Alzheimer's disease. New and improved inhibitors are warranted, mainly because of severe side effects of current drugs. In the present study, we have investigated if and how two enantiomeric inhibitors of AChE influence the overall dynamics of noncovalent complexes, using elastic incoherent neutron scattering. A fruitful combination of univariate models, including a newly developed non-Gaussian model for atomic fluctuations, and multivariate methods (principal component analysis and discriminant analysis) was crucial to analyze the fine details of the data. The study revealed a small but clear increase in the dynamics of the inhibited enzyme compared to that of the noninhibited enzyme and contributed to the fundamental knowledge of the mechanisms of AChE-inhibitor binding valuable for the future development of inhibitors.
ESTHER : Andersson_2018_J.Phys.Chem.B_122_8516
PubMedSearch : Andersson_2018_J.Phys.Chem.B_122_8516
PubMedID: 30110543

Title : N-Aryl-N'-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes - Knutsson_2017_Eur.J.Med.Chem_134_415
Author(s) : Knutsson S , Kindahl T , Engdahl C , Nikjoo D , Forsgren N , Kitur S , Ekstrom F , Kamau L , Linusson A
Ref : Eur Journal of Medicinal Chemistry , 134 :415 , 2017
Abstract : Vector control of disease-transmitting mosquitoes by insecticides has a central role in reducing the number of parasitic- and viral infection cases. The currently used insecticides are efficient, but safety concerns and the development of insecticide-resistant mosquito strains warrant the search for alternative compound classes for vector control. Here, we have designed and synthesized thiourea-based compounds as non-covalent inhibitors of acetylcholinesterase 1 (AChE1) from the mosquitoes Anopheles gambiae (An. gambiae) and Aedes aegypti (Ae. aegypti), as well as a naturally occurring resistant-conferring mutant. The N-aryl-N'-ethyleneaminothioureas proved to be inhibitors of AChE1; the most efficient one showed submicromolar potency. Importantly, the inhibitors exhibited selectivity over the human AChE (hAChE), which is desirable for new insecticides. The structure-activity relationship (SAR) analysis of the thioureas revealed that small changes in the chemical structure had a large effect on inhibition capacity. The thioureas showed to have different SAR when inhibiting AChE1 and hAChE, respectively, enabling an investigation of structure-selectivity relationships. Furthermore, insecticidal activity was demonstrated using adult and larvae An. gambiae and Ae. aegypti mosquitoes.
ESTHER : Knutsson_2017_Eur.J.Med.Chem_134_415
PubMedSearch : Knutsson_2017_Eur.J.Med.Chem_134_415
PubMedID: 28433681
Gene_locus related to this paper: anoga-ACHE1

Title : An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet - Allgardsson_2017_Molecules_22_
Author(s) : Allgardsson A , David Andersson C , Akfur C , Worek F , Linusson A , Ekstrom F
Ref : Molecules , 22 : , 2017
Abstract : Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by a rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for treatment of various cholinergic deficiencies, including Alzheimer's disease and myasthenia gravis. In a previous high throughput screening campaign, we identified the dye crystal violet (CV) as an inhibitor of AChE. Herein, we show that CV displays a significant cooperativity for binding to AChE, and the molecular basis for this observation has been investigated by X-ray crystallography. Two monomers of CV bind to residues at the entrance of the active site gorge of the enzyme. Notably, the two CV molecules have extensive intermolecular contacts with each other and with AChE. Computational analyses show that the observed CV dimer is not stable in solution, suggesting the sequential binding of two monomers. Guided by the structural analysis, we designed a set of single site substitutions, and investigated their effect on the binding of CV. Only moderate effects on the binding and the cooperativity were observed, suggesting a robustness in the interaction between CV and AChE. Taken together, we propose that the dimeric cooperative binding is due to a rare combination of chemical and structural properties of both CV and the AChE molecule itself.
ESTHER : Allgardsson_2017_Molecules_22_
PubMedSearch : Allgardsson_2017_Molecules_22_
PubMedID: 28867801
Gene_locus related to this paper: mouse-ACHE

Title : Discovery of Selective Inhibitors Targeting Acetylcholinesterase 1 from Disease-Transmitting Mosquitoes - Engdahl_2016_J.Med.Chem_59_9409
Author(s) : Engdahl C , Knutsson S , Ekstrom F , Linusson A
Ref : Journal of Medicinal Chemistry , 59 :9409 , 2016
Abstract : Vector control of disease-transmitting mosquitoes is increasingly important due to the re-emergence and spread of infections such as malaria and dengue. We have conducted a high throughput screen (HTS) of 17,500 compounds for inhibition of the essential AChE1 enzymes from the mosquitoes Anopheles gambiae and Aedes aegypti. In a differential HTS analysis including the human AChE, several structurally diverse, potent, and selective noncovalent AChE1 inhibitors were discovered. For example, a phenoxyacetamide-based inhibitor was identified with a 100-fold selectivity for the mosquito over the human enzyme. The compound also inhibited a resistance conferring mutant of AChE1. Structure-selectivity relationships could be proposed based on the enzymes' 3D structures; the hits' selectivity profiles appear to be linked to differences in two loops that affect the structure of the entire active site. Noncovalent inhibitors of AChE1, such as the ones presented here, provide valuable starting points toward insecticides and are complementary to existing and new covalent inhibitors.
ESTHER : Engdahl_2016_J.Med.Chem_59_9409
PubMedSearch : Engdahl_2016_J.Med.Chem_59_9409
PubMedID: 27598521
Gene_locus related to this paper: anoga-ACHE1 , mouse-ACHE

Title : The Nature of Activated Non-classical Hydrogen Bonds: A Case Study on Acetylcholinesterase-Ligand Complexes - Berg_2016_Chemistry_22_2672
Author(s) : Berg L , Mishra BK , Andersson CD , Ekstrom F , Linusson A
Ref : Chemistry , 22 :2672 , 2016
Abstract : Molecular recognition events in biological systems are driven by non-covalent interactions between interacting species. Here, we have studied hydrogen bonds of the CHY type involving electron-deficient CH donors using dispersion-corrected density functional theory (DFT) calculations applied to acetylcholinesterase-ligand complexes. The strengths of CHY interactions activated by a proximal cation were considerably strong; comparable to or greater than those of classical hydrogen bonds. Significant differences in the energetic components compared to classical hydrogen bonds and non-activated CHY interactions were observed. Comparison between DFT and molecular mechanics calculations showed that common force fields could not reproduce the interaction energy values of the studied hydrogen bonds. The presented results highlight the importance of considering CHY interactions when analysing protein-ligand complexes, call for a review of current force fields, and opens up possibilities for the development of improved design tools for drug discovery.
ESTHER : Berg_2016_Chemistry_22_2672
PubMedSearch : Berg_2016_Chemistry_22_2672
PubMedID: 26751405
Gene_locus related to this paper: mouse-ACHE

Title : Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6 - Allgardsson_2016_Proc.Natl.Acad.Sci.U.S.A_113_5514
Author(s) : Allgardsson A , Berg L , Akfur C , Hornberg A , Worek F , Linusson A , Ekstrom F
Ref : Proc Natl Acad Sci U S A , 113 :5514 , 2016
Abstract : Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme-sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.
ESTHER : Allgardsson_2016_Proc.Natl.Acad.Sci.U.S.A_113_5514
PubMedSearch : Allgardsson_2016_Proc.Natl.Acad.Sci.U.S.A_113_5514
PubMedID: 27140636
Gene_locus related to this paper: human-ACHE

Title : Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae: Functional Characterization and Comparisons with Vertebrate Orthologues - Engdahl_2015_PLoS.One_10_e0138598
Author(s) : Engdahl C , Knutsson S , Fredriksson SA , Linusson A , Bucht G , Ekstrom F
Ref : PLoS ONE , 10 :e0138598 , 2015
Abstract : Mosquitoes of the Anopheles (An.) and Aedes (Ae.) genus are principal vectors of human diseases including malaria, dengue and yellow fever. Insecticide-based vector control is an established and important way of preventing transmission of such infections. Currently used insecticides can efficiently control mosquito populations, but there are growing concerns about emerging resistance, off-target toxicity and their ability to alter ecosystems. A potential target for the development of insecticides with reduced off-target toxicity is the cholinergic enzyme acetylcholinesterase (AChE). Herein, we report cloning, baculoviral expression and functional characterization of the wild-type AChE genes (ace-1) from An. gambiae and Ae. aegypti, including a naturally occurring insecticide-resistant (G119S) mutant of An. gambiae. Using enzymatic digestion and liquid chromatography-tandem mass spectrometry we found that the secreted proteins were post-translationally modified. The Michaelis-Menten constants and turnover numbers of the mosquito enzymes were lower than those of the orthologous AChEs from Mus musculus and Homo sapiens. We also found that the G119S substitution reduced the turnover rate of substrates and the potency of selected covalent inhibitors. Furthermore, non-covalent inhibitors were less sensitive to the G119S substitution and differentiate the mosquito enzymes from corresponding vertebrate enzymes. Our findings indicate that it may be possible to develop selective non-covalent inhibitors that effectively target both the wild-type and insecticide resistant mutants of mosquito AChE.
ESTHER : Engdahl_2015_PLoS.One_10_e0138598
PubMedSearch : Engdahl_2015_PLoS.One_10_e0138598
PubMedID: 26447952
Gene_locus related to this paper: aedae-ACHE1 , anoga-ACHE1

Title : Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase - Andersson_2015_J.Comput.Aided.Mol.Des_29_199
Author(s) : Andersson CD , Hillgren JM , Lindgren C , Qian W , Akfur C , Berg L , Ekstrom F , Linusson A
Ref : J Comput Aided Mol Des , 29 :199 , 2015
Abstract : Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.
ESTHER : Andersson_2015_J.Comput.Aided.Mol.Des_29_199
PubMedSearch : Andersson_2015_J.Comput.Aided.Mol.Des_29_199
PubMedID: 25351962

Title : Divergent Structure-Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors - Andersson_2013_J.Med.Chem_56_7615
Author(s) : Andersson CD , Forsgren N , Akfur C , Allgardsson A , Berg L , Engdahl C , Qian W , Ekstrom F , Linusson A
Ref : Journal of Medicinal Chemistry , 56 :7615 , 2013
Abstract : The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure-activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE.
ESTHER : Andersson_2013_J.Med.Chem_56_7615
PubMedSearch : Andersson_2013_J.Med.Chem_56_7615
PubMedID: 23984975
Gene_locus related to this paper: mouse-ACHE

Title : Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: possible implications for the HI-6 antidote substrate specificity - Artursson_2013_Biochem.Pharmacol_85_1389
Author(s) : Artursson E , Andersson PO , Akfur C , Linusson A , Borjegren S , Ekstrom F
Ref : Biochemical Pharmacology , 85 :1389 , 2013
Abstract : Nerve agents such as tabun, cyclosarin and Russian VX inhibit the essential enzyme acetylcholinesterase (AChE) by organophosphorylating the catalytic serine residue. Nucleophiles, such as oximes, are used as antidotes as they can reactivate and restore the function of the inhibited enzyme. The oxime HI-6 shows a notably low activity on tabun adducts but can effectively reactivate adducts of cyclosarin and Russian VX. To examine the structural basis for the pronounced substrate specificity of HI-6, we determined the binary crystal structures of Mus musculus AChE (mAChE) conjugated by cyclosarin and Russian VX and found a conformational mobility of the side chains of Phe338 and His447. The interaction between HI-6 and tabun-adducts of AChE were subsequently investigated using a combination of time resolved fluorescence spectroscopy and X-ray crystallography. Our findings show that HI-6 binds to tabun inhibited Homo sapiens AChE (hAChE) with an IC50 value of 300muM and suggest that the reactive nucleophilic moiety of HI-6 is excluded from the phosphorus atom of tabun. We propose that a conformational mobility of the side-chains of Phe338 and His447 is a common feature in nerve-agent adducts of AChE. We also suggest that the conformational mobility allow HI-6 to reactivate conjugates of cyclosarin and Russian VX while a reduced mobility in tabun conjugated AChE results in steric hindrance that prevents efficient reactivation.
ESTHER : Artursson_2013_Biochem.Pharmacol_85_1389
PubMedSearch : Artursson_2013_Biochem.Pharmacol_85_1389
PubMedID: 23376121
Gene_locus related to this paper: mouse-ACHE

Title : Similar but different: thermodynamic and structural characterization of a pair of enantiomers binding to acetylcholinesterase - Berg_2012_Angew.Chem.Int.Ed.Engl_51_12716
Author(s) : Berg L , Niemiec MS , Qian W , Andersson CD , Wittung-Stafshede P , Ekstrom F , Linusson A
Ref : Angew Chem Int Ed Engl , 51 :12716 , 2012
Abstract : Take a closer look: Unexpectedly, a pair of enantiomeric ligands proved to have similar binding affinities for acetylcholinesterase. Further studies indicated that the enantiomers exhibit different thermodynamic profiles. Analyses of the noncovalent interactions in the protein-ligand complexes revealed that these differences are partly due to nonclassical hydrogen bonds between the ligands and aromatic side chains of the protein.
ESTHER : Berg_2012_Angew.Chem.Int.Ed.Engl_51_12716
PubMedSearch : Berg_2012_Angew.Chem.Int.Ed.Engl_51_12716
PubMedID: 23161758
Gene_locus related to this paper: mouse-ACHE

Title : Targeting acetylcholinesterase: identification of chemical leads by high throughput screening, structure determination and molecular modeling - Berg_2011_PLoS.One_6_e26039
Author(s) : Berg L , Andersson CD , Artursson E , Hornberg A , Tunemalm AK , Linusson A , Ekstrom F
Ref : PLoS ONE , 6 :e26039 , 2011
Abstract : Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by rapid hydrolysis of the neurotransmitter acetylcholine. Compounds inhibiting this enzyme can be used (inter alia) to treat cholinergic deficiencies (e.g. in Alzheimer's disease), but may also act as dangerous toxins (e.g. nerve agents such as sarin). Treatment of nerve agent poisoning involves use of antidotes, small molecules capable of reactivating AChE. We have screened a collection of organic molecules to assess their ability to inhibit the enzymatic activity of AChE, aiming to find lead compounds for further optimization leading to drugs with increased efficacy and/or decreased side effects. 124 inhibitors were discovered, with considerable chemical diversity regarding size, polarity, flexibility and charge distribution. An extensive structure determination campaign resulted in a set of crystal structures of protein-ligand complexes. Overall, the ligands have substantial interactions with the peripheral anionic site of AChE, and the majority form additional interactions with the catalytic site (CAS). Reproduction of the bioactive conformation of six of the ligands using molecular docking simulations required modification of the default parameter settings of the docking software. The results show that docking-assisted structure-based design of AChE inhibitors is challenging and requires crystallographic support to obtain reliable results, at least with currently available software. The complex formed between C5685 and Mus musculus AChE (C5685*mAChE) is a representative structure for the general binding mode of the determined structures. The CAS binding part of C5685 could not be structurally determined due to a disordered electron density map and the developed docking protocol was used to predict the binding modes of this part of the molecule. We believe that chemical modifications of our discovered inhibitors, biochemical and biophysical characterization, crystallography and computational chemistry provide a route to novel AChE inhibitors and reactivators.
ESTHER : Berg_2011_PLoS.One_6_e26039
PubMedSearch : Berg_2011_PLoS.One_6_e26039
PubMedID: 22140425
Gene_locus related to this paper: mouse-ACHE