How does a drug molecule find its target binding site
Yibing Shan,Eric T. Kim,Michael P. Eastwood,Ron O. Dror,Markus A. Seeliger,David E. Shaw,David E. Shaw +6 more
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TL;DR: The technique employed, which does not assume any prior knowledge of the binding site's location, may prove particularly useful in the development of allosteric inhibitors that target previously undiscovered binding sites.
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Abstract: Although the thermodynamic principles that control the binding of drug molecules to their protein targets are well understood, detailed experimental characterization of the process by which such binding occurs has proven challenging. We conducted relatively long, unguided molecular dynamics simulations in which a ligand (the cancer drug dasatinib or the kinase inhibitor PP1) was initially placed at a random location within a box that also contained a protein (Src kinase) to which that ligand was known to bind. In several of these simulations, the ligand correctly identified its target binding site, forming a complex virtually identical to the crystallographically determined bound structure. The simulated trajectories provide a continuous, atomic-level view of the entire binding process, revealing persistent and noteworthy intermediate conformations and shedding light on the role of water molecules. The technique we employed, which does not assume any prior knowledge of the binding site's location, may prove particularly useful in the development of allosteric inhibitors that target previously undiscovered binding sites.
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Citations
Complete reconstruction of dasatinib unbinding pathway from c-Src kinase by supervised molecular dynamics simulation method; assessing efficiency and trustworthiness of the method
TL;DR: Sarma et al. as mentioned in this paper used supervised molecular dynamics (SuMD) to reconstruct the unbinding pathway of the anticancer drug dasatinib from its target protein, the c-Src kinase.
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The Interaction of Metal Complexes with G-quadruplex DNA
A Spinello
- 12 Jan 2016
TL;DR: In this article, the interaction of metal complexes with G-quadruplex DNA was studied. And the relationship between metal complexes and DNA DNA was discussed in terms of the relation between metal and DNA.
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Roles of Accelerated Molecular Dynamics Simulations in Predictions of Binding Kinetic Parameters.
Jianzhong Chen,Wei Wang,Haibo Sun,Weikai He +3 more
TL;DR: This review focuses on the applications of enhanced sampling technologies in calculations of binding kinetics parameters and residence time of drugs and special attention is paid to accelerated molecular dynamics and Gaussian aMD simulations that have been adopted to predict the association or disassociation rate constant.
4
1.15 – Structural Chemogenomics Databases to Navigate Protein–Ligand Interaction Space
Georgi K. Kanev,Albert J. Kooistra,I.J.P. de Esch,C de Graaf +3 more
- 01 Jan 2017
TL;DR: Structural chemogenomics databases allow the integration and exploration of heterogeneous genomic, structural, chemical, and pharmacological data in order to extract useful information that is applicable for the discovery of new protein targets and biologically active molecules.
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