Supporting Information for:
Computer Simulations of Structure-Activity Relationships for hERG channel Blockers
Lars Boukharta,† Henrik Keränen,† Anna Stary-Weinzinger,‡ Göran Wallin,† Bert L. de Groot,§ Johan Åqvist*,†
†
Department of Cell and Molecular Biology, Uppsala University, Biomedical Center,
Box 596, SE-751 24 Uppsala, Sweden, ‡ Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria, § Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany * Corresponding author. Phone: +46 18 471 4109. Fax: +46 18 53 69 71. E-mail:
[email protected].
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Table S1. Ligand-surrounding energies, calculated relative LIE binding free energies and structural data from initial MD simulations of six candidate sertindole-hERG complexes.a Diastereoisomer
trans
cis
a
Scoring function
U lvdW −s
b
U lel− s
b
LIE ∆∆Gbind
RMSFb
RMSDc
Goldscore
-60.2
-113.7
0.0
0.56
2.17
Chemscore
-57.3
-114.5
+0.1
0.83
2.76
ASP
-60.9
-110.4
+1.5
0.61
2.36
Goldscore
-61.2
-107.6
+2.4
0.64
3.25
Chemscore
-62.9
-104.4
+3.7
0.90
1.73
ASP
-65.3
-106.4
+2.2
0.53
1.34
) and electrostatic ( U lel− s ) energies for the Ligand-surrounding van der Waals ( U lvdW −s
LIE bound (b) state of sertindole. The calculated relative binding free energies ( ∆∆Gbind ) are
obtained with the standard parametrization of LIE (46). The two potassium ions in the selectivity filter were weakly restrained by 1 kcal/(mol Å2) force constants in these initial simulations, wherefore the electrostatic interaction energies are different from the final ones in Table 2. The ligand-surrounding energies for the free (f) state of sertindole are
U lvdW −s U lel− s
f
f
= −40.2 , U lel− s
f
= −120.9 for the trans diastereomer and U lvdW −s
f
= −39.2 ,
= −120.3 for the cis diastereomer. All energies are in kcal/mol. bLigand heavy
atom RMSF in Å from the 2 ns MD simulations. cLigand heavy atom RMSD between MD starting and average structure in Å.
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Figure S1. Candidate sertindole docking solutions evaluated with MD simulations. (A) Sertindole trans diastereoisomer poses topscored by Goldscore (yellow), Chemscore (cyan) and ASP (magenta). (B) cis diastereoisomer poses topscored by Goldscore (yellow), Chemscore (cyan) and ASP (magenta). hERG in green α-carbon trace.
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Figure S2. (A) The Goldscore docking pose of compound 3 (yellow sticks), together with the MD average structure of 3 (cyan) when starting from the endpoint of the FEP calculation (magenta). (B) MD average structure of 3 (green) when starting from the Goldscore docking pose together with key interacting water molecules (yellow spheres). In cyan is the MD average structure of 3 when starting from the endpoint of the FEP calculation with interacting waters (red spheres).
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