1. VIRTUAL SCREENING STUDIES IN SEARCH OF
DOPAMINE D1 RECEPTOR LIGANDS AS ANTIPSYCHOTIC AGENTS
Adam Bucki,1 Marcin Feder,2 Maciej Pawłowski,1 and Marcin Kołaczkowski 1,2
1Jagiellonian University Collegium Medicum, Cracow, Poland; 2Adamed Ltd., Pieńków, Poland
adam.bucki@uj.edu.pl
Introduction Prospective virtual screening
Compound Structure GlideScore
% inhibition of control
specific binding*
ADN-0958 -7.25 99.2
ADN-2039 -7.86 100
ADN-1300 -9.87 100
ADN-1435 -8.22 100
ADN-3772 -11.81 100
Olanzapine - - 94
1. Kołaczkowski M., Bucki A., Feder M., Pawłowski M. Ligand-optimized homology models of D1 and D2
dopamine receptors: Application for virtual screening. J. Chem. Inf. Model. 2013, 53, 638-48.
2. Goldman-Rakic P. S., Castner S. A., Svensson T. H., Siever L. J., Williams G. V. Targeting the Dopamine D1
Receptor in Schizophrenia: Insights for Cognitive Dysfunction. Psychopharmacology (Berl.) 2004, 174, 3–16.
3. Kolaczkowski M., Marcinkowska M., Bucki A., Pawlowski M., Krukowski A., Rusiecki R., Siwek A., Wolak M.
Sulphonamide Derivatives of Alicyclic Amines for the Treatment of Central Nervous System Diseases.
WO2013001505 (A2), January 3, 2013.
Glide, Induced Fit Docking and Phase were implemented in Schrödinger Suite 2010, licensed for Jagiellonian University Collegium Medicum.
Virtual screening (VS) utilizing homology models of target receptors is a widely practised computational
approach of structure-based drug design (SBDD). It allows for a rapid and increasingly efficacious assessment
of biological activity of large libraries of chemical entities by high-throughput docking (HTD). We have
developed method of building reliable ligand-optimized homology models of D1 and D2 dopamine receptors
(D1R and D2R) and described several issues connected with their preparation and applicability in VS trials.1
Dopamine D1 receptors are involved in regulation of a variety of physiological processes affecting e.g.
cognition, behavior and motor functions. Therefore compounds possessing D1R activity are supposed to be
effective in therapy of cognition impairment and negative symptoms of schizophrenia.2
Dopamine D2 receptor ligands are well known to be effective in ameliorating positive symptoms of
schizophrenia.
Excessive
stimulation of D2R in
the limbic structures
Dopamine
transmission
deficit in frontal
cortex (D1R)
Rational design of novel D1R / D2R ligands is difficult because of distinct requirements for ligand spatial
configuration, resulting from their binding sites. We therefore carried out VS study of our in house database of
approximately 4200 compounds designed as monoaminergic receptors ligands in search of potential D1R
affinity.
Homology model preparation
Homology model validation – retrospective virtual screening
References
Active ligands library
100
80
60
40
20
For virtual screening trials, the database was enriched with a set of 340 high-affinity ligands of D1R.
Ligands displaying the lowest Ki values for D1R (< 100nM) were acquired from ChEMBL database.
VS decoy database
The database was prepared based on ZINC’s usual CNS permeable subset which contains 344 596
chemical entities, characterized by properties, which favor blood−brain barrier permeability (PSA: 0 − 60,
MW:150 − 400, and predicted xlogP: 1.5 − 2.7).
In order to exclude compounds considered to be unable to bind with monoaminergic receptors, the database
was filtered with a simple pharmacophore model, representative for monoaminergic receptor ligands. To
prepare this model, we selected several known antipsychotic drugs and found common pharmacophore
features employing Phase. The two most important were taken into account: positively charged amine group
and aromatic ring, situated in a distance of 6±1 Å from each other.
The designed database consisted of 17 196 compounds.
In vitro binding results
Conclusions
Homology models used in docking experiments performed well in VS studies. The obtained
enrichments in test VS were significantly higher than random distribution, particularly when using combined
results obtained from docking to 3 receptor models.
VS of 4200 compounds followed by in vitro binding assay of 411 selected compounds, resulted in 172
confirmed hits (hit rate 42%), verifying high capacity of VS tool in prediction of D1R affinity.
Amongst 5 distinct chemotypes, 4 may be considered as analogs of known antipsychotics displaying affinity
for D1R (i.e. olanzapine, risperidone, ziprasidone) and therefore being somehow obvious.
One of them - arylsulfonamide derivative of aryloxyethylazetidine was recognized as a novel scaffold
of D1R / D2R ligands. The representative compound (ADN-3772) displayed affinity for D1R equal 100%, while
for D2R – 99% (inhibition of control specific binding in the concentration of 1μM).
3 Functional assays revealed its
partial agonism efficacy in D2R (57% agonist effect and 97% antagonist effect in 1.0E-06 M concentration)
and antagonism to D1R.
Negative symptoms Positive symptoms
Optimization of binding site
through induced-fit docking
of active ligands
„RECONSTRUCTION
OF A LOCK ON A KEY”
Single ligand‐optimized model
EF1% = 17 BEDROC = 0.325
Combination of 3 best‐performing models
EF1% = 19 BEDROC = 0.330
Random distribution
0
0 10 20 30 40 50 60 70 80 90 100
% of active compounds found
% database
D1R/β2AR
sequence
alignment:
GeneSilico
Metaserver
Crude receptor
models:
Swiss-Model
Model
selection:
Glide XP VS criterion:
BEDROC
(1) EF1% = 17 BEDROC = 0.325
(2) EF1% = 17 BEDROC = 0.306
(3) EF1% = 19 BEDROC = 0.305
Library of 4190* original chemical entities:
compounds designed as monoaminergic receptors ligands,
potentially active in CNS disorders
*1213 structures published in 5 international patent applications
Automated docking to 3 homology models of D1R
(Glide XP)
Affinity of best-scored (Glidescore) 411 compounds was
determined by in vitro radioligand binding studies (Cerep, France)
172 compounds of substantial affinity for D1R identified (hit rate = 42%)
>90% inhibition of control specific binding at 1.0E-06 M
5 (out of 9 in total) clusters representing distinct chemotypes:
*Test compound concentration: 1.0E-06 M
Assay carried out in duplicate (n=2)
Hot ligand: SCH23390 (Ki = 1.3E-10 M)