Our efforts related to developing Structure-Based methods and targets related to the Mycobacterium tuberculosis have reached a significant milestone with the recent publication in Acta Crystallographica D of the three-dimensional structure of the essential enzyme Fructose-1,6-Bisphosphatase (MtFBPase). This target has been shown by members of our group to be essential for the growth of the Tb mycobacterium in non-glucose media, such as glycerol. The structure belongs to the Class II FBPase, distinct to the Class I FBPases found in mammalian organisms. Although related to the equivalent enzyme in E. coli, the structure of MtFBPase is most similar to the one present in Synechocystis (blue-green algae, strain 6803).
The structure has been published in Acta Cryst D as an open-access publication. The article can be found at:
Full citation is: Acta Crystallographica Section D: Structural Biology, 2018, Volume D74, pgs. 321-331.
My colleagues and I look forward to your comments.
I have spent some intense months devoted to writing several chapters for a future book entitled 'Optimizing Structure-Based Drug Discovery'. The project is ongoing and will probably be published sometime in 2018. by J. Wiley. However, the momentum was derailed by some urgent health issues in the family and I could not devote as much time as I would have liked on research: first things first!
However, I am happy to report that there are two items of interest for readers following the exploration of the use of Ligand Efficiency Indices in Drug Discovery.
1. A chapter in a book entitled 'Software and Techniques for Bio-Molecular Modeling' edited by Dr. Azat Mukhametov and published by the Austin Publishing Group. This book is an interesting new addition to the references of techniques, concepts and software in molecular modeling for drug discovery. Chapter 2 describes the latest developments on the AtlasCBS concept, in particular the use of KNIME workflows to produce atlas-like plots and planes using simple KNIME modules. The entire text of the book, courtesy of the Austin Publishing Group can be found within the 'AtlasCBS' tab.
2. An editorial in Drug Discovery Today, entitled 'Are SAR tables obsolete' was published recently (Dec. 16.2016) on line questioning the utility of that icon of Medicinal Chemistry papers, 'The SAR table'. The argument is made that currently, with all the knowledge available regarding the physicochemical properties of the compounds discussed in medicinal chemistry papers, it might be better to condense this information in some kind of 2D-diagram. The full text of the article is available in the 'Efficiency-Based Drug Discovery' tab.
In commemoration of the International Year of Crystallography (IYCr2014) many organizations, journals and institutions have prepared special activities. Among them, the National Research Council of Spain (CSIC) has sponsored the publication of a special issue of its official publication entitled Arbor. This number has recently appeared on line and among the contributions the first article is a review of the advances in macromolecular crystallography in the second half of the 20th century from a personal perspective, related to the development of Dr. Cele Abad-Zapatero as a professional scientist, from his boyhood years in Spain, soon after the end of the Spanish Civil war.
The article is accessible from the following link:
This article could be of interest to any budding scientist/crystallographer. Any interested reader should be able to download this or any other article from this special issue of
Arbor from the above website. Otherwise, copies can be requested from the author, from his e-mail address (see contact tab).
New blog posting at:
Image of the 'Chronophage Clock' in King's Parade in Cambridge
Among other things, this amazing clock is an homage to the
18th English clockmaker John Harrison who invented the
'grasshoper escapement' that allowed him to develop the
chronometers that permited the accurate determination of the
longitude at sea. A problem that had defied the most briliant minds
of his time. The clearly visible text in the lower ledge of the window is part of the full inscribed sentence on the window: Mundus transit et concupiscentia eius. This inscription is also present in the sun dial in one of the courtyards of Corpus Christi college. An reflection on the passing of time and our
desires and wishes.
A manuscript entitled 'Celebrating Macromolecular Crystallography: A Personal Perspective'
is currently in press in a special edition of the Journal ARBOR, Ciencia, Pensamiento y Cultura . This special issue is intended to commemorate the International Year of Crystallography (IYCr2014). This article is a review of the origins and advances of structural biology in the second half of the 20th Century from the personal perspective of the author, as he matured as a professional scientist. The journal ARBOR is a publication of the Natural Research Council of Spain (CSIC, Consejo Superior de Investigaciones Cientificas). It will be published as an open-access and so if any reader is interested it can probably be found in the internet. Contact me if you are interested and have difficulties in obtaining a copy. The publication is imminent.
Return to UIC early in April. Working with UIC colleagues on SBDD projects
Currently in Cambridge, UK. I am spending two months (Feb 1-April 1) in the neighborhood of Cambridge, UK continuing the research on the update and applications of the AtlastCBS to drug discovery, and also on the use of Ligand Efficiency Indices (LEIs) as part of a Multiple Parameter Optimization (MPO) strategy to expedite drug discovery and to make it more rigorous. The hosting institutions are Optibrium, Ltd and the European Bioinformatics Institute (EBI) at the Wellcome campus in Hixton (ChEMBL: Chemical Biology group).
Participated in a Structure-Based Drug Design workshop/course at the Institute Pasteur de Montevideo (Montevideo, Uruguay, Nov. 3-8). This was an intensive drug discovery workshop in collaboration with Profs. P. Michels (University of Edinburg) and W. Hol (University of Washington, Seattle). The course was focused on novel methods and techniques for drug discovery with emphasis on Neglected Diseases. You can find more about the course and the Institute Pasteur de Montevideo here. There were lectures during an entire week , posters, and also practical sessions reviewing several computational techniques, among them 'docking techniques'. There was also a full practical session devoted to the use of the AtlasCBS webserver.
(Images courtesy of Prof. W. Hol, University of Washington, Seattle).
Presented two talks at 23rd International Congress of Crystallography in Montreal, Canada (IUCr2014), Aug. 5-12. The first one was related to the presentation of Crystallography in a dramatic context. I reviewed the work that I have been doing on my own (Play: Picasso Meets Crystallography) and later in collaboration with Jill Campbell and Greg Gerhard (play: Bernal's Picasso) to present the concepts and history of Crystallography in a dramatic content. Further details can be found in the 'Bernal's Picasso' tab of this website. More details can also be found on the blog: www.crystaledges.org.
The second was related to the presence of symmetry in Art forms and
particularly in Rosewindows in Gothic Cathedrals. This presentation focused on the paper recently published in Acta Cryst vol. D70, published this past March. This is a theme that was mentioned before in this 'news and views' . The abstract of this presentation can also be presented in the www.crystaledges.org.
I will be happy to share more information if you are particularly interested.
Best wishes and enjoy the rest the summer.
There will be an upcoming paper in Future of Medicinal Chemistry (FMC), relating to the incorporation of the AtlasCBS and Ligand Efficiency framework into the StarDrop™ software (www.Optibrium.com). There have been quite a few publications in the field, particularly relating to the value of 'Ligand Efficiency Metrics' to guide drug discovery. Some of the papers are reviewed in the upcoming paper in FMC and perspectives for the future are presented.
Abad-Zapatero C, Champness EJ & Segall M. Alternative variables in drug discovery: promises and challenges. Future Med. Chem. 6(5), 577-593.
There is a pair of papers coming out in Acta Cryst D. One
about the structure of PurC from S. pneumoniae with my colleagues at UIC: N. Wolf,
M. Johnson and
Prof. L. Fung. A second, more intriguing, will be an essay on the series
'Notes of a
Protein Crystallographer' about the symmetry of the Rose Windows in
Cathedrals and the meaning of symmetry.
I'll provide details and links as soon as they come out.
I'll be in Cambridge, UK, Jan. 25-Feb. 4 working with my
colleagues at Optibrium on the implementation of the AtlasCBS software in
their StarDrop(TM) software
package. I should be back in Chicago, Feb. 8 and at the UIC campus soon
I will be in Paris, Jan. 20-24 for the events related to the
commemoration of the International Year of Crystallography (IYCr2014),
the IUCr and UNESCO. This is to celebrate the 100th year anniversary of the
unveiling of the very first crystallographic structure (NaCl) using X-rays
by the Bragg's (W.H. and W.L Bragg) in Cambridge, UK in 1913. Consult the
'crystaledges.org' for more details.
Leaving the UIC campus for a month stay in Europe.
Landing in Paris, Jan. 11, I'll be in Saarbrucken, Germany,
giving a Workshop on Protein Crystallography and Structure-Based
Drug Design in the laboratory of Prof. Rolf Hartmann, University of
Saarlandes, Department of Drug Optimization.
Happy New Year and best wishes to you and your family,
friends and colleagues for 2014 and beyond. See the last posting on the blog
for a reflective poem entitled 'Season's Lament' about Christmas trees.
Returned to UIC after first successful workshop about
the concepts and usage of the AtlasCBS concepts and tool
at the Helmholtz Institute of Pharmaceutical Research in Saarbruecken,
Germany (Sept. 30-Oct. 1).
The workshop was run in collaboration with the colleagues of Optibrium,
Ltd (UK) that now offers the AtlasCBS application as an add-on to their
software Stardrop(TM). Link
After the workshop, attended meeting in Getxo, Bilbao
(Spain) in honor of Jorge Navaza (Grenoble, France), recognizing his
contributions to the implementation of the Fast Rotation Function and
other mathematical and computational tools in crystallography and electron
microscopy. (See blog: Crystal Edges).
Currently at UIC. Blog 'Crystal Edges' inaugurated to
commemorate the International Year of Crystallography in 2014 (IYCr2014).
Please visit new leftmost tab 'Crystal Edges'.
Visiting professor at the University of Alcala de Henares (Madrid)
in the Department of Pharmacology, sponsored by the Foundation
Giner de los Rios to update, develop the AtlasCBS server and train
students and medicinal chemistry professionals.
Laboratory of Prof. F. Gago. Feb.-June.2013.
Recently published book: Ligand Efficiency Indices for Drug Discovery Towards an Atlas--Guided Paradigm See Flyer >>
Published paper on humidity control in macromolecular crystallography
Oliete et al. Elastic and inelastic diffraction changes upon variation of the relative humidity environment of PurE crystals. Acta Cryst. (2013) D69, 194-212.
Recent book summarizing the concepts and ideas related to Ligand
Efficiency Indices in Drug-Discovery:
'Ligand Efficiency Indices for Drug Discovery:
Towards and Atlas-Guided Paradigm'
Read More about the recent article in El Pais.
Cortes-Cabrera, A., Morreale, A., Gago, F. and C. Abad-Zapatero. AtlasCBS: a web server to map and explore chemico-biological space. J.
Comp. Aided Mol. Design. 2012. DOI 10.1007/s10822-012-9587-5. Read More
Contribution of indazolinone tautomers to kinase activity. Vasudevan A, Verzal MK, Villamil CI, Stewart KD, Abad-Zapatero C, Oie T,
Djuric SW. Bioorg Med Chem Lett. 2012 Jul 15;22(14):4502-5.
Exploration of diverse hinge-binding scaffolds for selective Aurora
Ji Z, Dai Y, Abad-Zapatero C, Albert DH, Bouska JJ, Glaser KB, Marcotte
PA, Soni NB, Magoc TJ, Stewart KD, Wei RQ, Davidsen SK, Michaelides MR. Bioorg Med Chem Lett. 2012 Jul 15;22(14):4528-31. Epub 2012 Jun 7.
Notes of a protein crystallographer: on the high-resolution structure of the PDB growth rate Abad-Zapatero, C. Acta Cryst. (2012). D68, 613-617
Article in El Pais commemorating the 40th anniversary of the PDB, at a meeting in Cold Spring Harbor Laboratory, Oct. 28-30, 2011.
AtlasCBS server beta-version available (see Tab).
Humidity control can compensate for the damage induced in protein crystals by alien solutions. C. Abad-Zapatero, R. Oliete, S. Rodriguez-Puente, J. Pous, L. Martinelli, M. E. Johnson and A. Guasch. Acta Crysta. (2011) F67, 1300-1308.
Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases William J. McClellan, Yujia Dai, Cele .Abad-Zapatero, Daniel H. Albert, Jennifer J. Bouska, Keith B. Glaser, Terry J. Magoc, Patrick A. Marcotte, Donald J. Osterling, Kent D. Stewart, Steven K. Davidsen, Michael R. Michaelides. Bioorganic & Medicinal Chemistry Letters 21 (2011) 5620–5624.
Crystallization and preliminary X-ray Characterization of the
glpX-encoded class II fructose-1,6-bisphosphatase from
Gutka, H., S.G. Franzblau, F. Movahedzadeh and Cele Abad-Zapatero. (2011). Acta Cryst. Section F, F67, 710-173.
Ligand Efficiency Indices (LEIs): More than a Simple Efficiency Yardstick. (2011). Cele Abad-Zapatero & D. Blassi. Review in Molecular Informatics. 30(2-3), 122-132.
Time-Trajectories in Efficiency Maps as Effective Guides for Drug Discovery Efforts. (2011). Serge Christmann-Franck, Daniel Cravo and Cele Abad-Zapatero. Molecular Informatics. 30 (2-3), 137-144.
Retrospective Mapping of SAR Data for TTR Protein in Chemico-Biological Space Using Ligand Efficiency Indices as a Guide to Drug Discovery Strategies. (2011). Daniel Blasi, Gemma Arsequell, Gregori Valencia, Joan Nieto, Antoni Planas, Marta Pinto, Nuria B. Centeno, Cele Abad-Zapatero, Jordi Quintana. Molecular Informatics. 30 (2-3), 161-167.
Recent article about 4th generation synchrotons appeared in the electronic version of the Spanish Newspaper 'El País' Feb. 15, 2011.
Destellos brillantes y ultracortos iluminarán la nueva biología estructural. More...
Recent publication of the AtlasCBS concept in Drug Discovery Today.
Ligand Efficiency Indices for an effective mapping of Chemico-Biological Space: the concept of an atlas-like representation. (2010). Drug Discovery Today. 15: 804-811. C. Abad-Zapatero, O. Perišić, J. Wass, A. P. Bento, J. Overington, B. Al-Lazikani, M. E. Johnson.
A novel non-ATP site in Protein Kinases of the MAP group (an interesting paper of SBDD).
Discovery and Characterization of non-ATP site Inhibitors of the Mitogen Activated Protein (MAP) Kinases. Chemical Biology. (2010). K. M. Comess, C. Sun, C. Abad-Zapatero, D. Borhani, E. Goedken, M. Argiriardi, D. R. Groebe, R. J. Gum, Y. Jia, J. E. Clampit, D. L. Haasch, H. T. Smith, S. Wang, D. Song, M. L. Coen, T. E. Cloutier, H. Tang, X. Cheng, C. Quinn, B. Liu, Z. Xin, G. Liu, E. H. Fry, V. Stoll, T. I. Ng, D. Banach, D. Marcotte, D. J. Burns, P. J. Hajduk. American Chemical Society. Chemical Biology. in press. (available online).
Current affiliation (May 1-July 31, 2011):
Visiting Professorship at the Center Molecular Biology Severo Ochoa (CBMSO), Madrid, Spain,
in the group of Bioinformatics of Dr. A. Morreale, in collaboration with Prof. F. Gago (University of Alcala de Henares, Madrid, Spain) to develop and implement the AtlasCBS server. Sponsored by the Spanish Ministry of Science and Technology.
U.S. PATENT NO. 7,795,248. Issue date, Sept 14, 2010.
Title: SUBSTITUTED 7,8-DIHYDRO-1H-PYRMIDO[4,5-B][1,4]DIAZEPIN-4-AMINES ARE NOVEL KINASE INHIBITORS. V. Gracias, C. Abad-Zapatero, Stevan W. Djuric et al. Novel protein kinase inhibitors.