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Binding Residence Time through Scaled Molecular Dynamics: A Prospective Application to hDAAO Inhibitors.

Abstract：

:Traditionally, a drug potency is expressed in terms of thermodynamic quantities, mostly Kd, and empirical IC50 values. Although binding affinity as an estimate of drug activity remains relevant, it is increasingly clear that it is also important to include (un)binding kinetic parameters in the characterization of potential drug-like molecules. Herein, we used standard in silico screening to identify a series of structurally related inhibitors of hDAAO, a flavoprotein involved in schizophrenia and neuropathic pain. We applied a novel methodology, based on scaled molecular dynamics, to rank them according to their residence times. Notably, we challenged the application in a prospective fashion for the first time. The good agreement between experimental residence times and the predicted residence times highlighted the procedure's reliability in both predictive and refinement scenarios. Additionally, through further inspection of the performed simulations, we substantiated a previous hypothesis on the involvement of a protein loop during ligand unbinding.

journal_name

J Chem Inf Model

journal_title

Journal of chemical information and modeling

authors

Bernetti M,Rosini E,Mollica L,Masetti M,Pollegioni L,Recanatini M,Cavalli A

doi

10.1021/acs.jcim.8b00518

subject

Has Abstract

pub_date

2018-11-26 00:00:00

pages

2255-2265

issue

11

eissn

1549-9596

issn

1549-960X

journal_volume

58

pub_type

杂志文章

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