Docking structurally similar analogues: Dealing with the false-positive.

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ID: 51667
2019
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Abstract
Analogue design forms one of the mainstays of new drug discovery. A fast-follow on approach is commonly used by modern day drug discoverers on the quest of the best in class. Monitoring close structural analogues of the pioneering drug by an algorithm such as docking is fraught with the risk of returning false positives. In this paper, we present the case of two near-pharmacophoric analogues of the JAK3 inhibitor Tasocitinib which give positive docking prediction despite being inactive. Post-processing the docked poses with MM/GBSA and parallel computation of electrostatic potential maps point towards a potential weakening of one of the crucial hydrogen bonds (hinge) within the ATP-binding pocket of JAK3. Perturbing the bound ligands by molecular dynamics (MD) simulations show the complexes to be unstable with the analogues losing their original hold on the protein within 1.2 ns. A short post MD simulation dramatically improves the prediction value of docking runs, especially when dealing with 'me-too' analogues.
Reference Key
khanjiwala2019dockingjournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Khanjiwala, Zahara;Khale, Anubha;Prabhu, Arati;
Journal journal of molecular graphics & modelling
Year 2019
DOI
S1093-3263(19)30335-3
URL
Keywords
jak3 electron density analogue design md simulations mm/gbsa per residue contribution

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