Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations

Van van der Westhuizen, Johan CStander, ARiley, DLPanayides, Jenny-Lee2023-05-122023-05-122022-03Van van der Westhuizen, J.C., Stander, A., Riley, D. & Panayides, J. 2022. Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations. Journal of Chemical Information and Modeling, 62(6). http://hdl.handle.net/10204/127761549-95961549-960XDOI: 10.1021/acs.jcim.1c01443http://hdl.handle.net/10204/12776Alzheimer's disease is the most common neurodegenerative disease and currently poses a significant socioeconomic problem. This study describes the uses of computer-aided drug discovery techniques to identify novel inhibitors of acetylcholinesterase, a target for Alzheimer's disease. High-throughput virtual screening was employed to predict potential inhibitors of acetylcholinesterase. Validation of enrichment was performed with the DUD-E data set, showing that an ensemble of binding pocket conformations is critical when a diverse set of ligands are being screened. A total of 720 compounds were submitted for in vitro screening, which led to 25 hits being identified with IC50 values of less than 50 µM. The majority of these hits belonged to two scaffolds: 1-ethyl-3-methoxy-3-methylpyrrolidine and 1H-pyrrolo[3,2-c]pyridin-6-amine both of which are noted to be promising compounds for further optimization. As various possible binding poses were suggested from molecular docking, molecular dynamics simulations were employed to validate the poses. In the case of the most active compounds identified, a critical, stable water bridge formed deep within the binding pocket was identified potentially explaining in part the lack of activity for subsets of compounds that are not able to form this water bridge.AbstractenAlzheimer's diseaseAcetylcholinesterase inhibitorsIn vitro screeningNeurodegenerative diseasesDiscovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulationsArticleVan van der Westhuizen, J. C., Stander, A., Riley, D., & Panayides, J. (2022). Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations. Journal of Chemical Information and Modeling, 62(6), http://hdl.handle.net/10204/12776Van van der Westhuizen, Johan C, A Stander, DL Riley, and Jenny-Lee Panayides "Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations." Journal of Chemical Information and Modeling, 62(6) (2022) http://hdl.handle.net/10204/12776Van van der Westhuizen JC, Stander A, Riley D, Panayides J. Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations. Journal of Chemical Information and Modeling, 62(6). 2022; http://hdl.handle.net/10204/12776.TY - Article AU - Van van der Westhuizen, Johan C AU - Stander, A AU - Riley, DL AU - Panayides, Jenny-Lee AB - Alzheimer's disease is the most common neurodegenerative disease and currently poses a significant socioeconomic problem. This study describes the uses of computer-aided drug discovery techniques to identify novel inhibitors of acetylcholinesterase, a target for Alzheimer's disease. High-throughput virtual screening was employed to predict potential inhibitors of acetylcholinesterase. Validation of enrichment was performed with the DUD-E data set, showing that an ensemble of binding pocket conformations is critical when a diverse set of ligands are being screened. A total of 720 compounds were submitted for in vitro screening, which led to 25 hits being identified with IC50 values of less than 50 µM. The majority of these hits belonged to two scaffolds: 1-ethyl-3-methoxy-3-methylpyrrolidine and 1H-pyrrolo[3,2-c]pyridin-6-amine both of which are noted to be promising compounds for further optimization. As various possible binding poses were suggested from molecular docking, molecular dynamics simulations were employed to validate the poses. In the case of the most active compounds identified, a critical, stable water bridge formed deep within the binding pocket was identified potentially explaining in part the lack of activity for subsets of compounds that are not able to form this water bridge. DA - 2022-03 DB - ResearchSpace DP - CSIR J1 - Journal of Chemical Information and Modeling, 62(6) KW - Alzheimer's disease KW - Acetylcholinesterase inhibitors KW - In vitro screening KW - Neurodegenerative diseases LK - https://researchspace.csir.co.za PY - 2022 SM - 1549-9596 SM - 1549-960X T1 - Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations TI - Discovery of novel Acetylcholinesterase inhibitors by virtual screening, in vitro screening, and molecular dynamics simulations UR - http://hdl.handle.net/10204/12776 ER -26583