Chemistry for Life: Innovative in Silico approaches
Alexandre G. de Brevern
DSIMB, INSERM UMR-S 665, Université Paris Diderot – Paris 7, INTS, 6, rue Alexandre Cabanel,
75015 Paris, France
Proteins are the basis of the majority of essential biological functions and also
pathologies. Knowledge on protein 3D structures is so essential for better understanding
protein functions. In the case of enzymes, determination of 3D structures has helped elucidate
why residues far apart in the sequence are involved in a given catalytic reaction. When
proteins are implicated in disease mechanisms, structures of targeted proteins are especially
useful for designing new drugs. Drug design has become extremely challenging due to the
necessity for high-throughput screening of new target proteins and to the emergence of drug
resistance. In the same way, protein dynamics has proved to be at the heart of catalysis
processes as it is involved in the regulation of turnover rates, in ligand/target recognition and
binding and in product release. Protein dynamics are strongly implicated in allosteric
regulation and more generally in molecular recognition processes and protein stability.
In silico approaches are so particularly appropriate to analyze protein structures,
protein dynamics to understand atomistic details of precise mechanisms and of great help to
drug design. At the French Institute for Blood Transfusion we used such approaches applied
to proteins implicated into pathologies, for biotechnological purpose and we are also deeply
implicated into innovative development for Fragment Based Drug Design in collaboration
with a start-up.
A first application has been done on a huge protein complex name αIIbβ3 integrin. We
have propose an explanation for the structure effect of the β3 Lys253Met substitution a
mutation impairing αIIbβ3 expression and leading to intense bleeding (Jallu et al., 2010). We
are currently using molecular dynamics to study the impact of polymorphisms. Different HPA
forms of αIIb and β3 were modeled and resulting structure characteristics of residue
accessibility, mobility, and electrostatic change were analyzed (Jallu et al., 2011). Recently,
we also analyzed the change of binding a protein to a DNA transcription factor implicated in
severe congenital anemia (Arnaud et al., 2010).
In the same way, we are working on a protein implicated in Plasmodium vivax
malarial infection, named DARC (de Brevern et al., 2005). We are designing a therapeutic
agent, taking this protein as a lead, to prevent the invasion of human red blood cells by
P.vivax. A library of camel VHHs able to find DARC has been product and in silico
approaches have been used to understand the binding process (Smolarek et al., 2010).
We collaborate also with MEDIT-SA start-up (http://www.medit-pharma.com/), a
company specialized in drug design. In this research area, MED-SuMo is a powerful
technology to detect and characterize similar local regions on protein surfaces (DoppeltAzeroual et al., 2010). With this approach, we have analyzed proteins (HSP90, topoisomerase
VI, and BCK) which all bind the drug radicicol, and underline precisely the binding problem
region (Doppelt-Azeroual et al., 2009). We have extended this methodology to Fragment
Based Drug Design and applied it to Eg5, a mitotic kinesin (Oguievetskaia, et al., 2009)
Arnaud L., Saison C., Helias V., Lucien N., Steschenko D., Giarratana M.-C., Prehu C.,
Foliguet B., Montout L., de Brevern A.G., Francina A., Ripoche P., Fenneteau O., Da Costa L.,
Peyrard T., Coghlan G., Zelinski T., Illum N., Birgens H., Tamary H., Iolascon A., Delaunay J.,
Tchernia G. & Cartron J.-P. (2010) A dominant mutation in the erythroid transcription factor gene
KLF1 causes a novel type of congenital dyserythropoietic anemia, The American Journal of Human
Genetics, 87(5):721-7.
de Brevern A.G.#, Wong H., Tournamille C., Colin Y., Le Van Kim C. & Etchebest C. (2005)
A structural model of a seven transmembrane helices receptor: The Duffy Antigen / Receptor for
Chemokine (DARC), Biochem Biophys Acta, 1724, 288-306.
Doppelt-Azeroual O.#, Koch K., Delfaud F., Moriaud F. & de Brevern A.G. (2010),
Classification of binding sites with MED-SuMo Multi approach: an application on Purinome, Protein
Science, 19(4):847-67.
Doppelt-Azeroual O.#, Koch K., Delfaud F., Moriaud F. & de Brevern A.G. (2010),
Classification of binding sites with MED-SuMo Multi approach: an application on Purinome, Protein
Science, 19(4):847-67.
Jallu V., Dusseaux M., Panzer S., Torchet M.F., Hezard N, Goudemand J., de Brevern A.G.,
Kaplan C. (2010) αIIb/β3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on
ITGA2B and ITGB3 mRNA splicing, expression, and structure-function. Human Mutation 31(3):23746.
Jallu V., Poulain P., Kaplan C., de Brevern A.G. (2011) 3D protein structure modeling: A tool
to provide insight into the platelet alloimmune response Transfusion Today, in press.
Smolarek D., Hattab C., Hassanzadeh-Ghassabeh G., Cochet S., Gutiérrez C., de Brevern
A.G., Udomsangpetch R., Picot J., Grodecka M., Wasniowska K., Muyldermans S., Colin Y., Le Van
Kim C., Czerwinski M., & Bertrand O. #, A recombinant dromedary antibody fragment (VHH)
directed against human Duffy Antigen Receptor for Chemokines, Cellular and Molecular Life
Sciences, 67(19):3371-87.