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  Blind prediction of distribution in the SAMPL5 challenge with QM based protomer and pKa corrections

Pickard, F. C., König, G., Tofoleanu, F., Lee, J., Simmonett, A. C., Shao, J., et al. (2016). Blind prediction of distribution in the SAMPL5 challenge with QM based protomer and pKa corrections. Journal of Computer-Aided Molecular Design, 1087-1100. doi:10.1007/s10822-016-9955-7.

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10822_2016_9955_MOESM1_ESM.pdf (Supplementary material), 713KB
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 Creators:
Pickard, Frank C.1, Author
König, Gerhard2, Author              
Tofoleanu, Florentina 1, Author
Lee, Juyong 1, Author
Simmonett, Andrew C.1, Author
Shao, Jihan3, Author
Ponder, Jay W.4, Author
Brooks, Bernard R.1, Author
Affiliations:
1Laboratory of Computational BiologyNational Institutes of Health – National Heart, Lung and Blood Institute, Rockville, USA, ou_persistent22              
2Research Department Thiel, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445590              
3Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA, ou_persistent22              
4Department of Chemistry, Washington University, St. Louis, USA, ou_persistent22              

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Free keywords: Free energy; Partition coefficients; Distribution coefficients; Non-Boltzmann; Bennett; Implicit solvent; SAMPL5; pKa; Protomer; Tautomer
 Abstract: The computation of distribution coefficients between polar and apolar phases requires both an accurate characterization of transfer free energies between phases and proper accounting of ionization and protomerization. We present a protocol for accurately predicting partition coefficients between two immiscible phases, and then apply it to 53 drug-like molecules in the SAMPL5 blind prediction challenge. Our results combine implicit solvent QM calculations with classical MD simulations using the non-Boltzmann Bennett free energy estimator. The OLYP/DZP/SMD method yields predictions that have a small deviation from experiment (RMSD = 2.3 log D units), relative to other participants in the challenge. Our free energy corrections based on QM protomer and pKa calculations increase the correlation between predicted and experimental distribution coefficients, for all methods used. Unfortunately, these corrections are overly hydrophilic, and fail to account for additional effects such as aggregation, water dragging and the presence of polar impurities in the apolar phase. We show that, although expensive, QM-NBB free energy calculations offer an accurate and robust method that is superior to standard MM and QM techniques alone.

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Language(s): eng - English
 Dates: 2016-06-212016-08-252016-09-19
 Publication Status: Published online
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1007/s10822-016-9955-7
 Degree: -

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Title: Journal of Computer-Aided Molecular Design
  Other : J. Comput.-Aided Mol. Des.
Source Genre: Journal
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Publ. Info: Switzerland : Springer International Publishing
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: 1087 - 1100 Identifier: ISSN: 0920-654X
CoNE: https://pure.mpg.de/cone/journals/resource/954925564670