Final Report Summary - EUROSTRUCT (European consolidation and promotion of research capacity in the area of structure-based drug discovery)
Executive summary:
The overriding objective of the EUROSTRUCT project was to unravel the research potential of the Structural biology and chemistry group (SBCG) and the Institute of Organic Pharmaceutical Chemistry (IOPC) of the National Hellenic Research Foundation. The general theme that underlies the work of SBCG is macromolecular structural biology and chemistry in which structures are used as the starting point for further studies on the mechanisms of catalysis, mechanisms of inhibition, regulation, molecular recognition, and structure-based drug design.
The main accomplishments of EUROSTRUCT were the setting up of a state-of-the-art X-ray facility, the recruiting of a large number of experienced personnel in order to build a critical mass of research capacity and the exchange of know-how and experience through trans-national secondments.
SBCG's research capacity has been reinforced by the strengthening of its human resources with the recruitment of three prominent scientists. In addition, scientific members of SBCG, have attended international conferences and presented research work with emphasis on structure-based drug discovery while the visits of leading scientific experts to Athens and secondments of SBCG researchers to research laboratories in Europe have all fostered the transfer of know-how and research experience to SBCG.
The X-ray facility together with protein purification, robotic crystallisation, Nuclear magnetic resonance (NMR) and Mass spectroscopy (MS) facilities as well as a computational facility all hosted in the IOPC, along with the increased transfer of knowledge, providing a much more integrated approach. Since the creation of the new facility, the number of protein targets under investigation has increased dramatically.
An international symposium and a five-day workshop, sponsored by EUROSTRUCT, were organised by SBCG. These events were very important in terms of development and maintenance of scientific excellence within SBCG by gathering information from experts from around the world. Moreover, they contributed effectively to increased visibility of SBCG and its research activities within the EU and elsewhere.
The scientific results of SBCG during the life of the EUROSTRUCT project are presented in 19 publications in peer reviewed scientific journals and 1 book chapter. In addition, SBCG members were participated in 21 international conferences or short term training events where their scientific results were presented in 22 poster and 16 oral presentations.
Project context and objectives:
The key objective of EUROSTRUCT seeks to unravel the potential of SBCG of the Institute of Organic and Pharmaceutical Chemistry (IOPC), at the National Hellenic Research Foundation (NHRF) by creating a centre of excellence in structural biology with emphasis on structure-based drug design and discovery.
The complete set of objectives is as follows:
- to set up a state-of the-art X-ray facility in the IOPC / NHRF and develop our computational infrastructure to meet our increasing needs;
- to build a critical mass of sustainable research capacity with the aid of experienced personnel;
- to extend the existing network of collaborations either with scientists within IOPC / NHRF and other national / international academic or research institutions in the frame of joint projects;
- to enhance the cooperation with research groups of international reputation in the field of structural biology and chemistry through secondments and invitations.
Project results:
The following papers reporting research work of SBCG and acknowledging the support of EUROSTRUCT were published in peer-referred journals.
1. Glucose-based spiro-isoxazolines: a new family of potent glycogen phosphorylase inhibitors. Benltifa M, Hayes JM, Vidal S, Gueyrard D, Goekjian PG, Praly JP, Kizilis G, Tiraidis C, Alexacou KM, Chrysina ED, Zographos SE, Leonidas DD, Archontis G, Oikonomakos NG. (2009) Biorg. Med. Chem. 17, 7368-7380.
2. Mapping the ribonucleolytic active site of bovine seminal ribonuclease. The binding of pyrimidinyl phosphonucleotide inhibitors. K Dossi, V.G. Tsirkone, J.M. Hayes, J. Matou?ek, P. Pou?ková, J. Sou?ek, M. Zadinova, S.E. Zographos, and D.D. Leonidas (2009) Eur. J. Med. Chem. 44, 4496-4508.
3. Inhibitor design to Ribonuclease A: The binding of two 5'phosphate uridine analogues V.G. Tsirkone, K. Dossi, C. Drakou, S.E. Zographos, M. Kontou and D.D. Leonidas (2009) Acta Crystallogr. F65, 671-677. Cover Story.
4. Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase case. E.D. Chrysina, É. Bokor; K.-M. Alexacou, M.-D. Charavgi, G.N. Oikonomakos, S. E. Zographos; D.D. Leonidas, N.G. Oikonomakos, and L. Somsák (2009) Tetrahedron Asymm. 20, 733-740.
5. Chrysina, E.D. The prototype of glycogen phosphorylase (2010) Mini Rev. Med. Chem. 10, 1093-10101.
6. Computation as a tool for glycogen phosphorylase inhibitor design. J.M. Hayes and D.D. Leonidas (2010) Mini Rev Med. Chem, 10, 1156-1174.
7. The binding of d-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: a new class of inhibitors. K.-M. Alexacou, A.-C. Tenchiu (Deleanu), E.D. Chrysina, M.-D. Charavgi, I.D. Kostas, S.E. Zographos, N.G. Oikonomakos, and D.D. Leonidas (2010) Biorg. Med. Chem. 18, 7911-7922.
8. 1-(3-Deoxy-3-fluoro-beta-d-glucopyranosyl) pyrimidine derivatives as inhibitors of glycogen phosphorylase b: Kinetic, crystallographic and modelling studies. Tsirkone VG, Tsoukala E, Lamprakis C, Manta S, Hayes JM, Skamnaki VT, Drakou C, Zographos SE, Komiotis D, Leonidas DD (2010) Biorg. Med. Chem. 18, 3413-3425.
9. Halogen-substituted (C-D-glucopyranosyl)-hydroquinone regioisomers: synthesis, enzymatic evaluation and their binding to glycogen phosphorylase. Alexacou KM, Zhang YZ, Praly JP, Zographos SE, Chrysina ED, Oikonomakos NG, Leonidas DD. (2011) Bioorg Med Chem. 19, 5125-5136.
10. Hayes JM, Skamnaki VT, Archontis G, Lamprakis C, Sarrou J, Bischler N, Skaltsounis A-L, Zographos SE, Oikonomakos NG, Kinetics, in silico docking, molecular dynamics and MM-GBSA binding studies on prototype indirubins, KT5720 and staurosporine as phosphorylase kinase ATP-binding site inhibitors: the role of water molecules examined, Proteins: Structure, Function & Bioinformatics (2011), 79, 703-719.
11. Kun, S., Nagy, G.Z. Tóth,M, Czecze L., Van Nhien, A.N. Docsa, T., Gergely, P., Charavgi, M.D. Skourti, P.V. Chrysina, E.D. Patonay, T., Somsák, L. (2011) Synthesis of variously coupled conjugates of D-glucose, 1,3,4-oxadiazole, and 1,2,3-triazole for inhibition of glycogen phosphorylase. Carbohydrate Res. 346, 1427-1438.
12. Chrysina, E.D. Chajistamatiou, A., Chegkazi, M. (2011) From structure-based to knowledge-based drug design through x-ray protein crystallography: sketching glycogen phosphorylase binding sites. Curr. Med. Chem. 18, 2620-22629.
13. The Hole Phenomenon of Halogen Atoms Forms the Structural Basis of the Strong Inhibitory Potency of C5 Halogen Substituted Glucopyranosyl Nucleosides towards Glycogen Phosphorylase b. Kantsadi AL, Hayes JM, Manta S, Skamnaki VT, Kiritsis C, Psarra AM, Koutsogiannis Z, Dimopoulou A, Theofanous S, Nikoleousakos N, Zoumpoulakis P, Kontou M, Papadopoulos G, Zographos SE, Komiotis D, Leonidas DD. (2012) ChemMedChem. In press doi: 10.1002/cmdc.201100533.
14. 3'-axial CH(2) OH substitution on glucopyranose does not increase glycogen phosphorylase inhibitory potency. QM/MM-PBSA calculations suggest why. Manta S, Xipnitou A, Kiritsis C, Kantsadi AL, Hayes JM, Skamnaki VT, Lamprakis C, Kontou M, Zoumpoulakis P, Zographos SE,Leonidas DD, Komiotis D. (2012) Chem Biol Drug Des. In press doi: 10.1111/j.1747-0285.2012.01349.
15. Drakou CE, Malekkou A, Hayes JM, Lederer CW, Leonidas DD, Oikonomakos NG, Lamond AI, Santama N, Zographos SE, ?hCINAP is an atypical mammalian nuclear adenylate kinase with an ATPase motif: Structural and functional studies, (2012), Proteins: Structure, Function & Bioinformatics 80, 206-220.
16. Tsitsanou KE, Thireou T, Drakou CE, Koussis K, Keramioti MV, Leonidas DD, Eliopoulos E, Iatrou K, Zographos SE (2012) Anopheles gambiae odorant binding protein crystal complex with the synthetic repellent DEET: implications for structure-based design of novel mosquito repellents Cellular Molecular Life Sci. 69, 283-97.
17. N-(4-Substituted-benzoyl)-N'-(d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods. Nagy V, Felföldi N, Kónya B, Praly JP, Docsa T, Gergely P, Chrysina ED, Tiraidis C, Kosmopoulou MN, Alexacou KM, Konstantakaki M, Leonidas DD, Zographos SE, Oikonomakos NG, Kozmon S, Tvaro?ka I, Somsák L. (2012) Bioorg Med Chem. 20, 1801-1816.
18. Dimarogona, M., Topakas, E., Christakopoulos, P., Chrysina, E.D. A new crystal structure of a Fusarium oxysporum GH10 xylanase reveals the presence of an extended loop on top of the catalytic cleft. Submitted to Acta Crystallogr. D.
19. Katerina E. Tsitsanou, Joseph M. Hayes, Maria Keramioti, Michalis Mamais, Costas Tiraidis, Kyra-Melinda Alexacou, Demetres D. Leonidas, Nikos G. Oikonomakos, Atsushi Kato, and Spyros E. Zographos. Sourcing the affinity of flavonoids for the glycogen phosphorylase inhibitor site via crystallography, kinetics and QM/MM-PBSA binding studies: comparison of chrysin and flavopiridol. Submitted to Journal of Computer-aided molecular design.
The following publication reporting research work of SBCG and acknowledging the support of EUROSTRUCT were published as Chapter in Book. 1. J.M. Hayes and G. Archontis MM-GB(PB)SA calculations of protein-ligand binding free energies?, published by InTech, Molecular Dynamics (2012), in press, ISBN 979-953-307-615-6.
Other short publications
1. Crystal structure of the nuclear factor hCINAP in complex with ADP refined to 1.8 resolution: Insights into the function of hCINAP. Spyros E. Zographos, Christina E. Drakou, Anna Malekkou, Niovi Santama, Joseph M. Hayes, Demetres D. Leonidas, Angus I. Lamond, A. Siafaka-kapadai and Nikos G. Oikonomakos (2008). MAX-lab Activity Report 2008, pp. 412-413. Report Online.
2. V.G. Tsirkone, K. Dossi, S.E. Zographos, C. Drakou, N.G. Oikonomakos, M. Kontou and D.D. Leonidas (2008). The binding of two 5? phosphate uridine analogues to Ribonuclease A: implications for structure based inhibitor design. MAX-lab Activity Report 2008, pp. 402-403. Report Online.
3. Katerina E. Tsitsanou, Christina E. Drakou and Spyros E. Zographos (2009) The structure of odorant binding protein 4 from Anopheles gambiae . MAX-lab Activity Report 2009, pp. 374-375. Report online.
4. Katerina E. Tsitsanou, Christina E. Drakou, Maria Keramioti and Spyros E. Zographos (2010). Crystal structure of odorant binding protein 4 from Anopheles gambiae complexed with N-Phenyl-1-1napthylamine. MAX-lab Activity Report 2010, pp. 382-383. ? Report Online.
5. V.T. Skamnaki, A. Katsandi, S. Manta, E. Tsoukala, S.E. Zographos, M. Kontou, P. Zoumpoulakis, D. Komiotis and D.D. Leonidas (2010). The binding of 1-(?-D-glucopyranosyl) pyrimidine derivatives to Glycogen phosphorylase b. MAX-lab Activity Report 2010, pp. 374-375. ? Report Online.
Potential impact:
Acquisition of state-of the art-equipment (in house X-ray facility) will boost the research currently performed in SBCG promoting IOPC / NHRF reputation. At the moment nine research projects are running in our group and all of them are structure oriented. As a consequence, their progress in terms of structure determination depends solely on the availability of X-rays. Particular emphasis should be given to the fact that most of these projects involve structure based design approaches where the crystal structure of the potential drugs with the macromolecular target is absolutely essential to map their interactions upon binding and improve their properties. Considering the emerging needs of our research work as reflected by the frequent trips to Synchrotron Radiation Sources at Large Scale Facilities all over Europe, it is evident that the installation of an in house X-ray facility in NHRF will have a tremendous impact on our research work.
Meanwhile, development of the computational aspect of our structure-based design projects will be a unique asset to the research carried out. Developing the computational potential and having an experienced researcher devoted to this work will definitely advance our research activities. All current projects require computational chemistry approaches. Only when this is accessible, our research group will be able to develop a solid framework for interpretation and thorough investigation of our macromolecular structures. Computer-aided design also serves to more efficiently propose improved ligand compounds in close cooperation with our synthetic organic chemistry collaborators. In addition, the presence of an experienced molecular biologist will boost SBCG researcher capacity towards more challenging macromolecules which usually require expertise and skills in particular expression systems (e.g. insect cells).
The above mentioned resources required by EUROSTRUCT will further our excellence and allow us to contribute both to research and society. It is within the bounds of our potential to design, synthesise and optimise specific and effective compounds with pharmaceutical relevance to the treatment of type 2 diabetes, neurodegenerative diseases, cancerous angiogenesis, and eosinophilic inflammatory syndromes. These diseases are among the 10 most occurring diseases in the developing world. Another main target for research are proteins present in olfactory antennae of the mosquito Anopheles gambiae, one of the main vectors of malaria. In addition there are a number of other proteins e.g. enzymes of biotechnological interest, under investigation at the SBCG, and the scope is not necessarily limited to drug design. The wide range of interests and subjects being investigated emphasising further the importance of unlocking SBCG's potential through EUROSTRUCT and pave the way to excellence at international level.
Building such a research capacity locally means encouraging excellent researchers to develop their careers in their home countries or regions. Support needs to be long-term to nurture the organic development of teams, centres, and networks. Crucial to boosting international capacity is the need to ensure that the research supported helps to consolidate local infrastructures and national institutions, and is geared to national priorities.
List of websites: http://www.eie.gr/nhrf/institutes/iopc/eu-projects/eurostruct/index-en.html
The overriding objective of the EUROSTRUCT project was to unravel the research potential of the Structural biology and chemistry group (SBCG) and the Institute of Organic Pharmaceutical Chemistry (IOPC) of the National Hellenic Research Foundation. The general theme that underlies the work of SBCG is macromolecular structural biology and chemistry in which structures are used as the starting point for further studies on the mechanisms of catalysis, mechanisms of inhibition, regulation, molecular recognition, and structure-based drug design.
The main accomplishments of EUROSTRUCT were the setting up of a state-of-the-art X-ray facility, the recruiting of a large number of experienced personnel in order to build a critical mass of research capacity and the exchange of know-how and experience through trans-national secondments.
SBCG's research capacity has been reinforced by the strengthening of its human resources with the recruitment of three prominent scientists. In addition, scientific members of SBCG, have attended international conferences and presented research work with emphasis on structure-based drug discovery while the visits of leading scientific experts to Athens and secondments of SBCG researchers to research laboratories in Europe have all fostered the transfer of know-how and research experience to SBCG.
The X-ray facility together with protein purification, robotic crystallisation, Nuclear magnetic resonance (NMR) and Mass spectroscopy (MS) facilities as well as a computational facility all hosted in the IOPC, along with the increased transfer of knowledge, providing a much more integrated approach. Since the creation of the new facility, the number of protein targets under investigation has increased dramatically.
An international symposium and a five-day workshop, sponsored by EUROSTRUCT, were organised by SBCG. These events were very important in terms of development and maintenance of scientific excellence within SBCG by gathering information from experts from around the world. Moreover, they contributed effectively to increased visibility of SBCG and its research activities within the EU and elsewhere.
The scientific results of SBCG during the life of the EUROSTRUCT project are presented in 19 publications in peer reviewed scientific journals and 1 book chapter. In addition, SBCG members were participated in 21 international conferences or short term training events where their scientific results were presented in 22 poster and 16 oral presentations.
Project context and objectives:
The key objective of EUROSTRUCT seeks to unravel the potential of SBCG of the Institute of Organic and Pharmaceutical Chemistry (IOPC), at the National Hellenic Research Foundation (NHRF) by creating a centre of excellence in structural biology with emphasis on structure-based drug design and discovery.
The complete set of objectives is as follows:
- to set up a state-of the-art X-ray facility in the IOPC / NHRF and develop our computational infrastructure to meet our increasing needs;
- to build a critical mass of sustainable research capacity with the aid of experienced personnel;
- to extend the existing network of collaborations either with scientists within IOPC / NHRF and other national / international academic or research institutions in the frame of joint projects;
- to enhance the cooperation with research groups of international reputation in the field of structural biology and chemistry through secondments and invitations.
Project results:
The following papers reporting research work of SBCG and acknowledging the support of EUROSTRUCT were published in peer-referred journals.
1. Glucose-based spiro-isoxazolines: a new family of potent glycogen phosphorylase inhibitors. Benltifa M, Hayes JM, Vidal S, Gueyrard D, Goekjian PG, Praly JP, Kizilis G, Tiraidis C, Alexacou KM, Chrysina ED, Zographos SE, Leonidas DD, Archontis G, Oikonomakos NG. (2009) Biorg. Med. Chem. 17, 7368-7380.
2. Mapping the ribonucleolytic active site of bovine seminal ribonuclease. The binding of pyrimidinyl phosphonucleotide inhibitors. K Dossi, V.G. Tsirkone, J.M. Hayes, J. Matou?ek, P. Pou?ková, J. Sou?ek, M. Zadinova, S.E. Zographos, and D.D. Leonidas (2009) Eur. J. Med. Chem. 44, 4496-4508.
3. Inhibitor design to Ribonuclease A: The binding of two 5'phosphate uridine analogues V.G. Tsirkone, K. Dossi, C. Drakou, S.E. Zographos, M. Kontou and D.D. Leonidas (2009) Acta Crystallogr. F65, 671-677. Cover Story.
4. Amide-1,2,3-triazole bioisosterism: the glycogen phosphorylase case. E.D. Chrysina, É. Bokor; K.-M. Alexacou, M.-D. Charavgi, G.N. Oikonomakos, S. E. Zographos; D.D. Leonidas, N.G. Oikonomakos, and L. Somsák (2009) Tetrahedron Asymm. 20, 733-740.
5. Chrysina, E.D. The prototype of glycogen phosphorylase (2010) Mini Rev. Med. Chem. 10, 1093-10101.
6. Computation as a tool for glycogen phosphorylase inhibitor design. J.M. Hayes and D.D. Leonidas (2010) Mini Rev Med. Chem, 10, 1156-1174.
7. The binding of d-glucopyranosyl-thiosemicarbazone derivatives to glycogen phosphorylase: a new class of inhibitors. K.-M. Alexacou, A.-C. Tenchiu (Deleanu), E.D. Chrysina, M.-D. Charavgi, I.D. Kostas, S.E. Zographos, N.G. Oikonomakos, and D.D. Leonidas (2010) Biorg. Med. Chem. 18, 7911-7922.
8. 1-(3-Deoxy-3-fluoro-beta-d-glucopyranosyl) pyrimidine derivatives as inhibitors of glycogen phosphorylase b: Kinetic, crystallographic and modelling studies. Tsirkone VG, Tsoukala E, Lamprakis C, Manta S, Hayes JM, Skamnaki VT, Drakou C, Zographos SE, Komiotis D, Leonidas DD (2010) Biorg. Med. Chem. 18, 3413-3425.
9. Halogen-substituted (C-D-glucopyranosyl)-hydroquinone regioisomers: synthesis, enzymatic evaluation and their binding to glycogen phosphorylase. Alexacou KM, Zhang YZ, Praly JP, Zographos SE, Chrysina ED, Oikonomakos NG, Leonidas DD. (2011) Bioorg Med Chem. 19, 5125-5136.
10. Hayes JM, Skamnaki VT, Archontis G, Lamprakis C, Sarrou J, Bischler N, Skaltsounis A-L, Zographos SE, Oikonomakos NG, Kinetics, in silico docking, molecular dynamics and MM-GBSA binding studies on prototype indirubins, KT5720 and staurosporine as phosphorylase kinase ATP-binding site inhibitors: the role of water molecules examined, Proteins: Structure, Function & Bioinformatics (2011), 79, 703-719.
11. Kun, S., Nagy, G.Z. Tóth,M, Czecze L., Van Nhien, A.N. Docsa, T., Gergely, P., Charavgi, M.D. Skourti, P.V. Chrysina, E.D. Patonay, T., Somsák, L. (2011) Synthesis of variously coupled conjugates of D-glucose, 1,3,4-oxadiazole, and 1,2,3-triazole for inhibition of glycogen phosphorylase. Carbohydrate Res. 346, 1427-1438.
12. Chrysina, E.D. Chajistamatiou, A., Chegkazi, M. (2011) From structure-based to knowledge-based drug design through x-ray protein crystallography: sketching glycogen phosphorylase binding sites. Curr. Med. Chem. 18, 2620-22629.
13. The Hole Phenomenon of Halogen Atoms Forms the Structural Basis of the Strong Inhibitory Potency of C5 Halogen Substituted Glucopyranosyl Nucleosides towards Glycogen Phosphorylase b. Kantsadi AL, Hayes JM, Manta S, Skamnaki VT, Kiritsis C, Psarra AM, Koutsogiannis Z, Dimopoulou A, Theofanous S, Nikoleousakos N, Zoumpoulakis P, Kontou M, Papadopoulos G, Zographos SE, Komiotis D, Leonidas DD. (2012) ChemMedChem. In press doi: 10.1002/cmdc.201100533.
14. 3'-axial CH(2) OH substitution on glucopyranose does not increase glycogen phosphorylase inhibitory potency. QM/MM-PBSA calculations suggest why. Manta S, Xipnitou A, Kiritsis C, Kantsadi AL, Hayes JM, Skamnaki VT, Lamprakis C, Kontou M, Zoumpoulakis P, Zographos SE,Leonidas DD, Komiotis D. (2012) Chem Biol Drug Des. In press doi: 10.1111/j.1747-0285.2012.01349.
15. Drakou CE, Malekkou A, Hayes JM, Lederer CW, Leonidas DD, Oikonomakos NG, Lamond AI, Santama N, Zographos SE, ?hCINAP is an atypical mammalian nuclear adenylate kinase with an ATPase motif: Structural and functional studies, (2012), Proteins: Structure, Function & Bioinformatics 80, 206-220.
16. Tsitsanou KE, Thireou T, Drakou CE, Koussis K, Keramioti MV, Leonidas DD, Eliopoulos E, Iatrou K, Zographos SE (2012) Anopheles gambiae odorant binding protein crystal complex with the synthetic repellent DEET: implications for structure-based design of novel mosquito repellents Cellular Molecular Life Sci. 69, 283-97.
17. N-(4-Substituted-benzoyl)-N'-(d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: Synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods. Nagy V, Felföldi N, Kónya B, Praly JP, Docsa T, Gergely P, Chrysina ED, Tiraidis C, Kosmopoulou MN, Alexacou KM, Konstantakaki M, Leonidas DD, Zographos SE, Oikonomakos NG, Kozmon S, Tvaro?ka I, Somsák L. (2012) Bioorg Med Chem. 20, 1801-1816.
18. Dimarogona, M., Topakas, E., Christakopoulos, P., Chrysina, E.D. A new crystal structure of a Fusarium oxysporum GH10 xylanase reveals the presence of an extended loop on top of the catalytic cleft. Submitted to Acta Crystallogr. D.
19. Katerina E. Tsitsanou, Joseph M. Hayes, Maria Keramioti, Michalis Mamais, Costas Tiraidis, Kyra-Melinda Alexacou, Demetres D. Leonidas, Nikos G. Oikonomakos, Atsushi Kato, and Spyros E. Zographos. Sourcing the affinity of flavonoids for the glycogen phosphorylase inhibitor site via crystallography, kinetics and QM/MM-PBSA binding studies: comparison of chrysin and flavopiridol. Submitted to Journal of Computer-aided molecular design.
The following publication reporting research work of SBCG and acknowledging the support of EUROSTRUCT were published as Chapter in Book. 1. J.M. Hayes and G. Archontis MM-GB(PB)SA calculations of protein-ligand binding free energies?, published by InTech, Molecular Dynamics (2012), in press, ISBN 979-953-307-615-6.
Other short publications
1. Crystal structure of the nuclear factor hCINAP in complex with ADP refined to 1.8 resolution: Insights into the function of hCINAP. Spyros E. Zographos, Christina E. Drakou, Anna Malekkou, Niovi Santama, Joseph M. Hayes, Demetres D. Leonidas, Angus I. Lamond, A. Siafaka-kapadai and Nikos G. Oikonomakos (2008). MAX-lab Activity Report 2008, pp. 412-413. Report Online.
2. V.G. Tsirkone, K. Dossi, S.E. Zographos, C. Drakou, N.G. Oikonomakos, M. Kontou and D.D. Leonidas (2008). The binding of two 5? phosphate uridine analogues to Ribonuclease A: implications for structure based inhibitor design. MAX-lab Activity Report 2008, pp. 402-403. Report Online.
3. Katerina E. Tsitsanou, Christina E. Drakou and Spyros E. Zographos (2009) The structure of odorant binding protein 4 from Anopheles gambiae . MAX-lab Activity Report 2009, pp. 374-375. Report online.
4. Katerina E. Tsitsanou, Christina E. Drakou, Maria Keramioti and Spyros E. Zographos (2010). Crystal structure of odorant binding protein 4 from Anopheles gambiae complexed with N-Phenyl-1-1napthylamine. MAX-lab Activity Report 2010, pp. 382-383. ? Report Online.
5. V.T. Skamnaki, A. Katsandi, S. Manta, E. Tsoukala, S.E. Zographos, M. Kontou, P. Zoumpoulakis, D. Komiotis and D.D. Leonidas (2010). The binding of 1-(?-D-glucopyranosyl) pyrimidine derivatives to Glycogen phosphorylase b. MAX-lab Activity Report 2010, pp. 374-375. ? Report Online.
Potential impact:
Acquisition of state-of the art-equipment (in house X-ray facility) will boost the research currently performed in SBCG promoting IOPC / NHRF reputation. At the moment nine research projects are running in our group and all of them are structure oriented. As a consequence, their progress in terms of structure determination depends solely on the availability of X-rays. Particular emphasis should be given to the fact that most of these projects involve structure based design approaches where the crystal structure of the potential drugs with the macromolecular target is absolutely essential to map their interactions upon binding and improve their properties. Considering the emerging needs of our research work as reflected by the frequent trips to Synchrotron Radiation Sources at Large Scale Facilities all over Europe, it is evident that the installation of an in house X-ray facility in NHRF will have a tremendous impact on our research work.
Meanwhile, development of the computational aspect of our structure-based design projects will be a unique asset to the research carried out. Developing the computational potential and having an experienced researcher devoted to this work will definitely advance our research activities. All current projects require computational chemistry approaches. Only when this is accessible, our research group will be able to develop a solid framework for interpretation and thorough investigation of our macromolecular structures. Computer-aided design also serves to more efficiently propose improved ligand compounds in close cooperation with our synthetic organic chemistry collaborators. In addition, the presence of an experienced molecular biologist will boost SBCG researcher capacity towards more challenging macromolecules which usually require expertise and skills in particular expression systems (e.g. insect cells).
The above mentioned resources required by EUROSTRUCT will further our excellence and allow us to contribute both to research and society. It is within the bounds of our potential to design, synthesise and optimise specific and effective compounds with pharmaceutical relevance to the treatment of type 2 diabetes, neurodegenerative diseases, cancerous angiogenesis, and eosinophilic inflammatory syndromes. These diseases are among the 10 most occurring diseases in the developing world. Another main target for research are proteins present in olfactory antennae of the mosquito Anopheles gambiae, one of the main vectors of malaria. In addition there are a number of other proteins e.g. enzymes of biotechnological interest, under investigation at the SBCG, and the scope is not necessarily limited to drug design. The wide range of interests and subjects being investigated emphasising further the importance of unlocking SBCG's potential through EUROSTRUCT and pave the way to excellence at international level.
Building such a research capacity locally means encouraging excellent researchers to develop their careers in their home countries or regions. Support needs to be long-term to nurture the organic development of teams, centres, and networks. Crucial to boosting international capacity is the need to ensure that the research supported helps to consolidate local infrastructures and national institutions, and is geared to national priorities.
List of websites: http://www.eie.gr/nhrf/institutes/iopc/eu-projects/eurostruct/index-en.html
