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New paper in Journal of Chemical Theory and Computation


Happy new year to all my readers!

Having a new paper published is always a matter of happiness for this computational chemist but this time I’m excedingly excited about anouncing the publishing of a paper in the Journal of Chemical Theory and Computation, which is my highest ranked publication so far! It also establishes the consolidation of our research group at CCIQS as a solid and competitive group within the field of theoretical and computational chemistry. The title of our paper is “In Silico design of monomolecular drug carriers for the tyrosine kinase inhibitor drug Imatinib based on calix- and thiacalix[n]arene host molecules. A DFT and Molecular Dynamics study“.

In this article we aimed towards finding a suitable (thia-) calix[n]arene based drug delivery agent for the drug Imatinib (Gleevec by Novartis), which is a broadly used powerful Tyrosine Kinase III inhibitor used in the treatment of Chronic Myeloid Leukaemia and, to a lesser extent, Gastrointestinal Stromal Tumors; although Imatinib (IMB) exhibits a bioavailability close to 90% most of it is excreted, becomes bound to serum proteins or gets accumulated in other tissues such as the heart causing several undesired side effects which ultimately limit its use. By using a molecular capsule we can increase the molecular weight of the drug thus increasing its retention, and at the same time we can prevent Imatinib to bind, in its active form, to undesired proteins.

We suggested 36 different calix and thia-calix[n]arenes (CX) as possible candidates; IMB-CX complexes were manually docked and then optimized at the B97D/6-31G(d,p) level of theory; Stephan Grimme’s B97D functional was selected for its inclusion of dispersion terms, so important in describing π-π interactions. Intermolecular interaction energies were calculated under the Natural Bond Order approximation; a stable complex was needed but a too stable complex would never deliver its drug payload! This brings us to the next part of the study. A monomolecular drug delivery agent must be able to form a stable complex with the drug but it must also be able to release it. Molecular Dynamics simulations (+100 ns) and umbrella sampling methods were used to analyse the release of the drug into the aqueous media.

Optimized geometries for all complexes under study (B97D/6-31G*)

Optimized geometries for the 20 most stable complexes under study (B97D/6-31G*)

Potential Mean Force profiles for the four most stable complexes for position N1 and  N2 from the QM simulations are shown below (Red, complexes in the N1 position, blue, N2 position). These plots, derived from the MD simulations  give us an idea of the final destination of the drug respect of the calixarene carrier. In the next image, the three preferred structures (rotaxane-like; inside; released) for the final outcome of the delivery process are shown. The stability of the complexes was also assessed by calculating the values of ΔG binding through the use of the Poisson equations.

PMF for the most stable compounds

PMF for the most stable compounds

General MD simulation final structures

General MD simulation final structures

Thanks to my co-authors Maria Eugenia Sandoval-Salinas and Dr. Rodrigo Galindo-Murillo for their enormous contributions to this work; without their hard work and commitment to the project this paper wouldn’t have been possible.

Summer Internships


This week has been a happy one since four new additions to our staff have been made, at least for the summer, that is. Paulina, Eliana, Javier and Daniel have come to our lab from various different towns across the nation to spend six weeks working hard in small projects related to our lines of research; namely theoretical drug carriers design. This time the drug under study is known as GTP or 3-phenyl(1H-[1]benzofuro[3,2]pyrazole and calixarenes will once again act as the potential carriers.

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Left to Right: Daniel, Javier, Paulina and Eliana
(Summer Interns – 2013)

They all came as part of the Dolphin Research Summer Program (link in Spanish only) in which college students spend a few weeks doing research in the lab of their choosing. This is the first time I participate as a tutor and I find it a great opportunity for young students to get familiar with certain aspects of science they wont learn inside school.

So far these past three days have been quite intense with them learning how to edit and submit a Gaussian calculation in a Linux environment. I’ve already taught them about geometry optimizations, frequency analysis, (natural) population analysis and Fukui reactivity indices calculation. There is much more to learn still, of course, but so far so good. I believe the major drawback so far has been their own eagerness since they’d like to have all the data imediately! Unfortunately they’ll have to wait for their initial calculations to converge. We started this week by doing some simple analysis of all the properties described above for the Cytosine-Guanine base pair at the B97D/6-31+G(d,p) level of theory. Luckily their calculation crashed promptly, and I find that lucky because that gave me the opportunity to teach them how to relaunch a failed calculation, which, unfortunatelly will happen more often than not.

So, welcome guys! Thanks for choosing this lab for doing your internships. I hope you find our research interesting and motivating, may this be the first step into a full time research career. Also, kudos to the Dolphin Staff for helping promote science in young Mexican students. Stay tuned for a guest post from all of them once they finish their time here.

XIth Mexican Reunion on Theoretical Physical Chemistry


For over a decade these meetings have gathered theoretical chemists every year to share and comment their current work and to also give students the opportunity to interact with experienced researchers, some of which in turn were even students of Prof. Robert Parr, Prof. Richard Bader or Prof. Per Olov Löwdin. This year the Mexican Meeting on Theoretical Physical Chemistry took place last weekend in Toluca, where CCIQS is located. You can find links to this and previous meetings here. We participated with a poster which is presented below (in Spanish, sorry) about our current research on the development of calixarenes and tia-calixarenes as drug carriers. In this particular case, we presented our study with the drug IMATINIB (Gleevec as branded by Novartis), a powerful tyrosinkynase inhibitor widely employed in the treatment of Leukaemia.

The International Journal of Quantum Chemistry is dedicating an issue to this reunion. As always, this meeting posed a great opportunity to reconnect with old friends, teachers, and colleagues as well as to make new acquaintances; my favourite session is still the beer session after all the seminars! Kudos to María Eugenia “Maru”  Sandoval-Salinas for this poster and the positive response it generated.

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