Abstract：
:Binding affinity prediction with implicit solvent models remains a challenge in virtual screening for drug discovery. In order to assess the predictive power of implicit solvent models in docking techniques with Amber scoring, three generalized Born models (GBHCT, GBOBCI, and GBOBCII) available in Dock 6.7 were utilized, for determining the binding affinity of a large set of β-cyclodextrin complexes with 75 neutral guest molecules. The results were compared to potential of mean force (PMF) free energy calculations with four GB models (GBStill, GBHCT, GBOBCI, and GBOBCII) and to experimental data. Docking results yield similar accuracy to the computationally demanding PMF method with umbrella sampling. Neither docking nor PMF calculations reproduce the experimental binding affinities, however, as indicated by a small Spearman rank order coefficient (∼0.5). The binding energies obtained from GB models were decomposed further into individual contributions of the binding partners and solvent environments and compared to explicit solvent simulations for five complexes allowing for rationalizing the difference between explicit and implicit solvent models. An important observation is that the explicit solvent screens the interaction between host and guest much stronger than GB models. In contrast, the screening in GB models is too strong in solutes, leading to overestimation of short-range interactions and too strong binding. It is difficult to envision a way of overcoming these two opposite effects.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Zhang H,Yin C,Yan H,van der Spoel Ddoi
10.1021/acs.jcim.6b00418subject
Has Abstractpub_date
2016-10-24 00:00:00pages
2080-2092issue
10eissn
1549-9596issn
1549-960Xjournal_volume
56pub_type
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