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Modeling of halogen-protein interactions in co-solvent molecular dynamics simulations Ying Yang, Amr H. Mahmoud, and Markus A Lill J. Chem. Inf. Model., Just Accepted Manuscript • DOI: 10.1021/acs.jcim.8b00806 • Publication Date (Web): 10 Dec 2018 Downloaded from http://pubs.acs.org on December 17, 2018
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Journal of Chemical Information and Modeling
Modeling of Halogen-Protein Interactions in Co-Solvent Molecular Dynamics Simulations Ying Yang, Amr H. Mahmoud, and Markus A. Lill∗ Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47906, United States E-mail:
[email protected] Phone: (765) 496-9375. Fax: (765)) 494-1414
Abstract Co-solvent molecular dynamics (MD) simulations have recently become successful approaches in structure-based drug design but neglect important interactions such as halogen bonding. To be able to successfully model compound libraries containing halogenated ligands using co-solvent simulations, we investigate the use of halogenated benzene probes in co-solvent simulations on the two test systems human cathepsin L (hCatL) and the Y220C mutant of the tumor suppressor p53 (p53-Y220C) . Our studies demonstrate that halogenated benzene probes indeed can unambiguously identify halogen-bonding interaction sites in the binding pocket and show superior correlation and ranking performance compared to standard co-solvent approaches.
Introduction Co-solvent molecular dynamics (MD) simulations 1 have recently become important tools in structure-based drug design, for example, for identifying binding hotspots, 2–5 assessing
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druggability of binding sites, 6 identifying allosteric or cryptic sites, 3,7–9 and assisting the scoring and ranking of ligands. 4,10–12 Commonly, a small set of probes is used to represent aromatic, aliphatic, hydrogen-bond donor, hydrogen-bond acceptor, and charged functional groups of potentially interacting ligands. Other important interactions, such as halogenbonding, are not incorporated in standard co-solvent simulations. Halogen substituents, however, are frequently used in pharmaceutics to increase binding affinity via halogen bonding (XB) 13 or improve pharmacokinetic properties such as oral bioavailability 14 and blood-brain barrier permeability. 15 Halogen bonding is a noncovalent interaction between the electrophilic region on the halogen atom (also called σ-hole) and a nucleophilic region of an acceptor group such as a Lewis base or a π system. 13,16–19 Halogen bond strength increases with the magnitude of the σ-hole in the order of Cl
