Lösin bakımından zengin tekrar kinaz 2 G2019S'ye karşı inhibitörlerin çok yöntemli hesaplamalı değerlendirmesi Parkinson hastalığı için mutant

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Leucine-rich repeat kinase 2 G2019S mutant (LRRK2 G2019S) is a potential target for Parkinson's disease therapy. In this work, the computational evaluation of the LRRK2 G2019S inhibitors was conducted via a combined approach which contains a preliminary screening of a large database of compounds via similarity and pharmacophore, a secondary selection via structure-based affinity prediction and molecular docking, and a rescoring treatment for the final selection. MD simulations and MM/GBSA calculations were performed to check the agreement between different prediction methods for these inhibitors. 331 experimental ligands were collected, and 170 were used to build the structure-activity relationship. Eight representative ligand structural models were employed in similarity searching and pharmacophore screening over fourteen million compounds. The process for selecting proper molecular descriptors provides a successful sample which can be used as a general strategy in QSAR modelling. The rescoring used in this work presents an alternative useful treatment for ranking and selection.

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