Forsgren N

References (7)

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 : Dual Reversible Coumarin Inhibitors Mutually Bound to Monoamine Oxidase B and Acetylcholinesterase Crystal Structures - Ekstrom_2022_ACS.Med.Chem.Lett_13_499
Author(s) : Ekstrom F , Gottinger A , Forsgren N , Catto M , Iacovino LG , Pisani P , Binda C
Ref : ACS Med Chem Lett , 13 :499 , 2022
Abstract : Multitarget directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies. The synergistic inhibition of monoamine oxidase B (MAO B) and acetylcholinesterase (AChE) is believed to provide a potentiated effect in the treatment of Alzheimer's disease. Among previously reported micromolar or sub-micromolar coumarin-bearing dual inhibitors, compound 1 returned a tight-binding inhibition of MAO B (Ki = 4.5 microM) and a +5.5 C increase in the enzyme Tm value. Indeed, the X-ray crystal structure revealed that binding of 1 produces unforeseen conformational changes at the MAO B entrance cavity. Interestingly, 1 showed great shape complementarity with the AChE enzymatic gorge, being deeply buried from the catalytic anionic subsite (CAS) to the peripheral anionic subsite (PAS) and causing significant structural changes in the active site. These findings provide structural templates for further development of dual MAO B and AChE inhibitors.
ESTHER : Ekstrom_2022_ACS.Med.Chem.Lett_13_499
PubMedSearch : Ekstrom_2022_ACS.Med.Chem.Lett_13_499
PubMedID: 35300078
Gene_locus related to this paper: mouse-ACHE

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 : 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 : 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