Blinded predictions of distribution coefficients in the SAMPL5 challenge.
In the context of the SAMPL5 challenge water-cyclohexane distribution coefficients for 53 drug-like molecules were predicted. Four different models based on molecular dynamics free energy calculations were tested. All models initially assumed only one chemical state present in aqueous or organic phases. Model A is based on results from an alchemical annihilation scheme; model B adds a long range correction for the Lennard Jones potentials to model A; model C adds charging free energy corrections; model D applies the charging correction from model C to ionizable species only. Model A and B perform better in terms of mean-unsigned error ([Formula: see text] D units - 95 % confidence interval) and determination coefficient [Formula: see text], while charging corrections lead to poorer results with model D ([Formula: see text] and [Formula: see text]). Because overall errors were large, a retrospective analysis that allowed co-existence of ionisable and neutral species of a molecule in aqueous phase was investigated. This considerably reduced systematic errors ([Formula: see text] and [Formula: see text]). Overall accurate [Formula: see text] predictions for drug-like molecules that may adopt multiple tautomers and charge states proved difficult, indicating a need for methodological advances to enable satisfactory treatment by explicit-solvent molecular simulations.
EaStCHEM School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, EH9 3FJ, UK.
Stefano
S
Bosisio
EaStCHEM School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, EH9 3FJ, UK.
Antonia S J S
AS
Mey
EaStCHEM School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, EH9 3FJ, UK. mail@julienmichel.net.
Julien
J
Michel
D003198:Computer Simulation; D003510:Cyclohexanes / Q000737:chemistry; D062126:Databases, Chemical; D008956:Models, Chemical; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011789:Quantum Theory; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D003510:Cyclohexanes; D004364:Pharmaceutical Preparations; D012997:Solvents; D014867:Water; C506365:Cyclohexane
Distribution coefficient; SAMPL5
J Comput Chem. 2004 Jul 15;25(9):1157-74
15116359
Comb Chem High Throughput Screen. 2013 Dec;16(10):817-25
24168238
J Med Chem. 1977 Jan;20(1):53-8
13215
Acta Pol Pharm. 2013 Jan-Feb;70(1):3-18
23610954
Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
11259830
J Chem Theory Comput. 2013 Jul 9;9(7):3084-95
26583988
J Mol Biol. 2013 Nov 15;425(22):4569-83
23896298
J Chem Phys. 2006 Jun 14;124(22):224501
16784292
J Comput Aided Mol Des. 2017 Jan;31(1):61-70
27503495
J Chem Theory Comput. 2013 Jan 8;9(1):461-469
23316124
J Comput Aided Mol Des. 2016 Nov;30(11):945-958
27718028
J Chem Phys. 2006 Mar 28;124(12):124106
16599661
J Biomol Screen. 2009 Dec;14(10):1245-50
19822883
J Phys Chem B. 2015 Oct 8;119(40):12912-20
26339862
Bioinformatics. 2013 Apr 1;29(7):845-54
23407358
J Chem Theory Comput. 2015 Apr 14;11(4):1864-74
26574392
J Comput Aided Mol Des. 2016 Nov;30(11):927-944
27677750
J Comput Chem. 2014 Jan 30;35(3):227-43
24249099
J Comput Chem. 2013 Jan 30;34(3):187-97
22996256
J Comput Aided Mol Des. 2010 Apr;24(4):259-79
20455007
J Comput Aided Mol Des. 2010 Aug;24(8):639-58
20509041
Phys Chem Chem Phys. 2014 Mar 14;16(10):4465-77
24469595
J Med Chem. 1980 Jun;23(6):682-4
7392035
J Phys Chem B. 2007 Nov 15;111(45):13052-63
17949030
J Chem Phys. 2008 Sep 28;129(12):124105
19045004