Curriculum
Vitae
Personal
Data
Name
Dr. Csaba Hetényi
Year and Country of
Birth
1976,
Present Position
Bolyai
Fellow
Department of Genetics,
Web http://xray.bmc.uu.se/~csaba/
Education
PhD Pharmacy
Faculty of Pharmacy, University of Szeged, Hungary, 2002 Summa cum laude.
Dissertation: Blind
docking: A novel approach of locating binding sites of potential drugs on macromolecules
(Unusual applications of AutoDock)
MSc Qualified Chemist
Faculty of Science,
With honours.
Thesis:
Synthesis and computer-aided structural analysis of
Work
Experience, Fellowships
2009-2012
Bolyai
Fellow. Sponsor:
Department of
Genetics,
2009
Eötvös
Travel Fellowship.
Sponsor:
Molecular
Biophysics Group, Department of Cell and
Molecular Biology,
Collaborator: Prof.
David van der Spoel.
2006-2008 Senior
Researcher. Sponsors:
Foundation Innove &
2005
Eötvös
Travel Fellowship.
Sponsor:
Molecular
Biophysics Group, Department of Cell and
Molecular Biology,
Collaborator: Prof.
David van der Spoel.
2003-2006 Békésy
Fellow. Sponsor:
Hungarian Ministry of Education.
Department of
Biochemistry,
2002-2003
Postdoctoral
Fellow. Sponsor: European
Union.
Research Training
Network: Imagetox.
Department of Chemical
Physics,
Collaborators: Prof.
Mati Karelson, Dr. Uko Maran.
2000-2001
Researcher.
Employer: TRIPEP AB,
1999-2000
Researcher.
Sponsors:
Department
of Biochemistry,
Supervisor:
Prof. Stellan Hjertén.
1999-2001
PhD
student.
Sponsor:
Department
of Medical Chemistry,
Supervisor:
Prof. Botond Penke.
1999
Special prize of the Hungarian
Chemical Society (for my MSc Thesis).
Professional
Activities
Reviewing
- Referee
of scientific journals. J Am
Chem Soc, Proteins, Expert Opin Drug Discov, J Comput-Aided Mol Design, J Chem
Inf Model, Bioorgan Med Chem,
Mini Rev Med Chem
- Opponent
and member of doctoral committees.
Teaching
- Research-informed
teaching. Details can be found in Section “Teaching
Achievements”.
- Medical
chemistry. Foundation chemistry teaching (general, physical, organic,
inorganic) for medical students during my PhD
studies.
Research
- Biophysical
and medicinal chemistry.
- Structure-based
calculation of thermodynamics of molecular interactions.
- Molecular
modeling and simulation of structures of macromolecules.
- Computer-aided drug
design.
- Molecular pathomechanism of diseases.
- Structural
bioinformatics. Computational chemistry.
- Quantitative
structure-activity relationships.
- Molecular mechanics,
molecular dynamics.
- Application of
quantum chemical methods.
- Chromatography and
capillary electrophoresis (formerly).
Funding
Fellowships
A list of awarded
fellowships is provided in Section Work
experience, Fellowships.
Scientific leadership
of project
Modern post-graduate
training in molecular technology on international level and improvement of the
competitiveness of research and development (No.
1.0101-0310). Sponsors: Innove Foundation (www.innove.ee),
and
(2.3 million
EEK)
Link: http://xray.bmc.uu.se/~csaba/poster_eng.pdf
Scientometrics
Number of Refereed
Papers: 22
Number of Patents: 3
Sum of Impact Factors
of the Papers:
86
Sum of the Times
Cited: 525
Hirsch-index: 13
Research
achievements
Blind docking. Computational molecular docking is one of the most
advanced atomic resolution techniques of structural calculation of ligand-target complexes (Allen, Form finds function. Nat Chem Biol, 3, 452-3, 2007). Docking calculations are
generally restricted to the close surrounding of the hypothesized binding site.
However, there are cases where even the approximate location of the binding site
of a ligand is unknown.
To extend the docking methodology for
these problematic cases, we developed parameters and tested the blind docking
(BD) approach for peptide ligands (ARTICLE 5*). During BD the entire surface of
the target protein is mapped. BD results both the binding position and
conformation of the ligand at atomic resolution. The
best sites can be selected due to binding affinity values based on the
protein-docked ligand complex structures. BD has been extended and verified for smaller, drug-like ligands and for large protein targets (ARTICLE 15), as well. ARTICLES 5 and 15 were selected for the covers
of the respective journals and have already received more than one hundred
citations including applications of BD for mapping of e.g. allosteric binding sites. We have also applied the BD
approach to develop aggregation inhibitors of the ß-amyloid peptide of Alyheimer’s disease (ARTICLES 4, 6, 11) and for mapping a
prerequisite binding site of inhibitor blebbistatin on
myosin II (ARTICLE 10).
Calculation of binding
affinity. Precise
estimation of equilibrium binding affinity, i.e. the binding free energy
(deltaG) of a ligand to a targeted macromolecule is a
central issue of structure-based drug discovery. deltaG can be calculated
directly from docked ligand-protein complex structures
with scoring functions including enthalpic (deltaH)
and entropic (deltaS) binding contributions according to deltaG=deltaH–TdeltaS,
where T is the thermodynamic temperature. Although there are various deltaG
calculators for smaller ligands, the calculation of
deltaG for large, peptide ligands is still
challenging. Using the deltaH terms of a modified scoring function we calculated
the deltadeltaG, i.e. the difference between deltaGs
of a large inhibitor peptide bound to two different types of trypsin (ARTICLE 12) and also analyzed the energetic
contributions of each amino acid to the peptide-trypsin interactions. Our findings were featured on the
cover of the Journal of Molecular Biology. On the basis of these promising
results we prepared a comprehensive study on a series of 50 biologically
important peptide ligands (ARTICLE 14) using a combination of deltaH
terms of the AutoDock3 scoring function and ligand-based molecular descriptors of the deltaS
contributions. Excellent correlations were achieved between calculated and
experimental deltaG values. In a recent study, we successfully estimated
deltaGs (ARTICLE 17) of agonists to an adrenergic
receptor target, as well.
Structural
calculations. In collaborations I have calculated various protein
(-ligand) structures using molecular dynamics and
docking methods. For example, in a recent study (ARTICLE 20) we investigated the interaction of
the 1st PHD finger of human Autoimmune Regulator (AIRE, grey) protein with histone H3 peptide (orange). AIRE plays an important role in
Autoimmune Polyendocrinopathy Ectodermal Dystrophy (APECED). To explore the molecular
basis of this disease I constructed and optimized the AIRE PHD1-H3 complex using
structural analogues and molecular dynamics calculations and also studied the
effect of methylation. My model was verifyied by heteronuclear NMR
mapping of the binding site and mutagenesis studies along with fluorescence
spectroscopy and isothermal titration calorimetry
(ITC) measurements. Our results revealed a new role for the PHD finger in the
recognition of non-methylated histones which correlates with transcriptional activation
mediated by AIRE in vivo. I have also
contributed to structural calculations of different myosin systems (ARTICLE 13, 16, 18) and the H-bonding in
Schiff bases (ARTICLE 7).
*As numbered in my List of
Publications.
Teaching
achievements
Course development
1. Title:
Introduction
to structural modeling of bioactive molecules. Levels: BSc,
MSc, PhD. Type: Lectures & Seminars. Language: English. Actively taught: 4 semesters.
Contents.
1)
Visualization of macromolecules. Structural editing and
comparisons. Programs VMD and PyMol. 2)
An introduction to macromolecular structures.
Web
page: http://xray.bmc.uu.se/~csaba/msc.html
Course development
2. Title:
Molecular interactions in
biological systems. Level:
PhD. Type: Lectures & Seminars.
Language: English. Actively taught: 3
semesters. Contents. 1) Selected principles of classical thermodynamics.
2) Selected principles of statistical thermodynamics. 3) Energy and force (conservativity and additivity). 4)
Model potentials. 5) Generation of conformational ensembles with molecular
dynamics (MD). 6) The free energy perturbation (FEP) and the thermodynamic
integration (TI) methods. 7) The linear interaction energy method (LIE). 8)
Scoring and empirical free energy functions of drug binding. 9) Hit-to-lead
optimization. Lead-likeness and drug-likeness. 10)
Druggability of targets and drug efficiency.
Problematic cases of drug design (AIDS, Alzheimer's
disease).
Web
page: http://hermes.chem.ut.ee/~csaba/phd.html