Predictive Power of Molecular Dynamics Receptor Structures in Virtual Screening

By Sara E. Nichols, R. Baron, A. Ivetac, James Andrew McCammon. 2011

90 citations recorded by the source corpus.

Molecular dynamics (MD) simulation is a well-established method for understanding protein dynamics. Conformations from unrestrained MD simulations have yet to be assessed for blind virtual screening (VS) by docking. This study presents a critical analysis of the predictive power of MD snapshots to this regard, evaluating two well-characterized systems of varying flexibility in ligand-bound and unbound configurations. Results from such VS predictions are discussed with respect to experimentally determined structures. In all cases, MD simulations provide snapshots that improve VS predictive power over known crystal structures, possibly due to sampling more relevant receptor conformations. Additionally, MD can move conformations previously not amenable to docking into the predictive range.

Subfields: Computational Theory and Mathematics, Materials Chemistry, Molecular Biology, Evaluation & Benchmarks, Computational Chemistry & Drug Discovery

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Citations in the corpus

Molecular Docking and Structure-Based Drug Design Strategies (2015, background): “As a result, the trajectory and temporal evolution of a ligand-receptor complex can be examined [103].”
Latest developments in molecular docking: 2010–2011 in review (2013, result): “[40] Whereas the best MD snapshots systematically performed better than crystal structures in all cases, a signi ﬁ cant number of snapshots gave less predictive VS results than the least predictive crystal structures, especially for the least ﬂ exible system considered.”
Accounting for receptor flexibility and enhanced sampling methods in computer aided drug design (2013, background): “applicable protocol for a priori determining the most predictive structures from the simulations has not been determined (34).”