6FSD
Mus musculus acetylcholinesterase in complex with 2-(4-Biphenylyloxy)-N-[3-(1-piperidinyl)propyl]-acetamide hydrochloride (10)
Summary for 6FSD
| Entry DOI | 10.2210/pdb6fsd/pdb |
| Descriptor | Acetylcholinesterase, 2-(4-phenylphenoxy)-~{N}-(3-piperidin-1-ylpropyl)ethanamide, 2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXYL, ... (6 entities in total) |
| Functional Keywords | inhibitor, hydrolase, acetylcholinesterase, protein binding |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 2 |
| Total formula weight | 121685.58 |
| Authors | Knutsson, S.,Engdahl, C.,Kumari, R.,Kindahl, T.,Forsgren, N.,Lindgren, C.,Kitur, S.,Kamau, L.,Ekstrom, F.,Linusson, A. (deposition date: 2018-02-19, release date: 2018-10-31, Last modification date: 2024-11-06) |
| Primary citation | Knutsson, S.,Engdahl, C.,Kumari, R.,Forsgren, N.,Lindgren, C.,Kindahl, T.,Kitur, S.,Wachira, L.,Kamau, L.,Ekstrom, F.,Linusson, A. Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency. J.Med.Chem., 61:10545-10557, 2018 Cited by PubMed 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. PubMed: 30339371DOI: 10.1021/acs.jmedchem.8b01060 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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