Blog Archives

Mexican Phys.Chem. Meeting XVth edition 


For the fifth year in a row my research group has participated in this traditional meeting on theoretical and computational chemistry, now at the beautiful city of Merida in southeastern Mexico.

Several distinguished international guests included Profs. Jose Luis Mendoza (Florida State University), Adrián Roitberg (University of Florida), Vincent Ortiz (Auburn University) and Paul Ayers (McMaster U. Canada); Their contributions rounded up nicely those of household names like Drs. Alberto Vela, Gabriel Merino (CINVESTAV) (the latter was also the main organizer), Jesus Hernández-Trujillo (UNAM), Jose Luis Gazquez (UAM-I), Óscar Jimenez (Guanajuato), and so many others who were also present.

My students presented four posters summarized below:

1) Maru Sandoval and Gustavo Mondragón on Photosynthesis, particularly the search for exciton transference mechanisms in both natural and theoretical arrangements of photosynthetic pigments. Some very exciting results have been observed; their publication is really near.


2) Raúl Torres and Gustavo Mondragón presented their work on arsenic removing calixarenes, published earlier this year, and the extension of said work to As(III) acids. Graphene oxide is now considered in our simulations as per the experimental work of our colleagues, Prof. Reyes Sierra and Prof. Eddie Lopez-Honorato.


3) Marco Diaz, Guillermo Caballero, Gustavo Mondragón and Raúl Torres had this poster on the calculation of sigma holes as descriptors for predicting pka values in organic acids. Their +1600 calculations project has found the best levels of theory (and ruled out some like B3LYP, of course) with some nice correlations. Yet, much work is still to be done but we’re on the right track.


4) Durbis Castillo presented his work on molecular docking and dynamics of a large library of HIV-1 entry inhibitors for which he uses the suite MAESTRO as a continuation of another project of ours. His enormous library is now in the hundredths of thousands and although we’re facing some technical difficulties, Durbis is thriving in his search. This is our first serious attempt towards a more mature drug discovery project; a manuscript should be ready in the first part of next year.


This guys and the rest of the lab who weren’t present are the ones who make our research flourish and they’ve all earned a day or two at the beach!

Here’s to fifteen more years of RMFQT!

Back in Pécsi Tudomanyegyetem (Hungary)


I’m so glad to be back in Pécs, Hungary, at the lab of my good old friend Prof. Dr. Sándor Kunsági. It has been seven years since I was last here and so many things have happened and yet it feels like yesterday I was walking through these halls.

As part of an agreement between the science councils of both Mexico and Hungary, our research proposal on the development of macrocyclic-based therapeutic agents for capturing micotoxins and other molecules was selected for financing. As before, the theoretical section will be handled by us, namely to some extent by Marco Diaz as part of his BSc thesis, while the experimental part will be handled by the group from Prof. Kunsagi’s lab and Dr. Lemli Beáta‘s. I’m very excited about living for a month here in Pécs but also about having a close friend, to whom I owe so much, working with me in an experimental-theoretical project that will further advance both our researches and careers. It was in fact the work of Profs. Kunsagi here in Pécs and Silaghi in Cluj, Romania, which got me interested in the supramolecular chemistry of calixarenes.

Lets hope we can manage to keep this collaboration between our labs going on for many years to come. For the sake of humor here are some old and new photographs.

New Paper in JIPH – As(V)@calix[n]arenes


As part of an ongoing collaboration with the University of Arizona (UA) and the Center for Advanced Research and Studies (CINVESTAV – Saltillo), we are looking into the use of calix[n]arenes for bio-remediation agents capable to extract Arsenic (V) and (III) species from water. Water contamination by arsenic is a pressing issue in northern Mexico and the southern US, therefore any efforts aiming to their elimination has strong social and health repercussions.

As in previous studies, all calixarenes were optimized along with their corresponding guests within the cavity, namely H3AsO4, H2AsO4 and HAsO42- at the DFT level with the so-called Minnesota functionals by Truhlar and Cao, M06-2X/6-31G(d,p) level of theory. Interaction energies were calculated through the NBODel procedure. Calixarenes with R = SO3H and PO3H are the most promising leads. This study is now publishes in the Journal of Inclusion Phenomena and Macrocyclic Chemistry (DOI 10.1007/s10847-016-0617-0) as an online first article.

This article is also the first to be published by our undergraduate (and almost grad student in a month) Gustavo Mondragón who took this project on a side to his own research on photosynthesis.

Now my colleagues in Arizona and Saltillo, Prof. Reyes Sierra and Dr. Eddie López, respectively, will work on the experimental side of the project. Further calculations are being undertaken to extend this study to As(III) and to the use of other potential extracting materials such as metallic nanoparticles to which calixarenes could be covalently linked.

A new chemist is graduated


It is with great pleasure that I announce the graduation of another member of our research group: Luis Enrique “Kike” Aguilar defended his BSc thesis yesterday and is now counting the days left for the Autumn when he’ll move to the Netherlands for a masters in computational chemistry.

Luis Enrique, Kike, calculated the interaction energies of 144 different inclusion complexes where calix and thia-calix[n]arenes were once again the chosen hosts (36 of them) and two drugs for the treatment of chronic myeloid leukemia (CML), namely Sorafenib and Bosutinib, were the guests.

The publication of the corresponding article in which we once again were fortunate enough to count with the collaboration of Dr. Rodrigo Galindo from Utah University in the molecular dynamics section, is still pending but we’re confident enough that it wont take much longer until it’s out there.

Kike is a very diligent student with great learning skills, I’m sure he’ll succeed in any enterprise he sets himself off.  Congratulations, Kike! Thanks for being a part of our research but more importantly for being a part of our community.


    

WATOC 2014 – Virtual edition


I had a blast last week at WATOC2014 in Santiago de Chile! It was a wonderful opportunity to find old friends, meet new ones and listen to some exciting research done around the world, as well as some of the classics such as Pekka Pyykkö, who was awarded the Schrödinger medal. I decided to share my talk on SlideShare.com but also here because I found at WATOC that many many people seem to like this little space of mine! I was shocked, flattered but mostly happy to know that this little blog of mine is well regarded.

So, without further ado, here is my presentation at WATOC2014, please read the captions on each image for context. Feel free to make any comments, sharing or liking. Thanks for clicking!

Self explanatory :)

Self explanatory 🙂

Administration of a drug follows one of these two extreme pharmacokinetic pathways. Either way, drugs accumulate in non-target tissues, are wasted and cause undesired secondary effects.

Administration of a drug follows one of these two extreme pharmacokinetic pathways. Either way, drugs accumulate in non-target tissues, are wasted and cause undesired secondary effects.

Ideally, a drug should arrive to the target tissue. Several polymolecular drug carriers have been developed.

Ideally, a drug should arrive to the target tissue. Several polymolecular drug carriers have been developed.

In terms of monomolecular carriers, cyclodextrines have shown moderate success.

In terms of monomolecular carriers, cyclodextrines have shown moderate success.

Calixarenes offer a more chemically-tunable alternative.

Calixarenes offer a more chemically-tunable alternative.

We decided to go with drugs for the treatment of chronic myeloid leukemia

We decided to go with drugs for the treatment of chronic myeloid leukemia

.

.

Interaction energies were calculated with the NBODel approach, in which elements of the Fock Matrix common to two molecular fragments are deleted

Interaction energies were calculated with the NBODel approach, in which elements of the Fock Matrix common to two molecular fragments are deleted

This deletion yields a new Fock matrix which is re-diagonalized; the increase in energy is ascribed to the interaction between both fragments.

This deletion yields a new Fock matrix which is re-diagonalized; the increase in energy is ascribed to the interaction between both fragments.

GTP was a small place to start (chemical space blocked due to animation lost in translation)

GTP was a small place to start (chemical space blocked due to animation lost in translation)

Interaction energies obtained

Interaction energies obtained

Hydrogen bonds and pi - pi interactions account for the large interaction energies

Hydrogen bonds and pi – pi interactions account for the large interaction energies

Diapositiva13

Detail of the interactions in some of the obtained geometries

 

 

MD simulations show the progress of the "release" process.

MD simulations show the progress of the “release” process.

So we moved to a larger drug with more degrees of freedom (and a comercial one too)

So we moved to a larger drug with more degrees of freedom (and a comercial one too)

Chemical space increased regard to the one used with GTP.

Chemical space increased regard to the one used with GTP.

In both cases, two insertion modes were considered.

In both cases, two insertion modes were considered.

Some results...

Some results…

100ns of MD show three kinds of structures (inserted, partially released and totally released)

100ns of MD show three kinds of structures (inserted, partially released and totally released)

PMF US - the profile of release tells us if the carrier is way too strong to be a carrier at all.

PMF US – the profile of release tells us if the carrier is way too strong to be a carrier at all.

Where do we go from here?

Where do we go from here?

Second generation CML drugs; however Bosutinib poses a funny challenge

Second generation CML drugs; however Bosutinib poses a funny challenge

A comercial error has released two isomers to the market, only one of them actually works. CAN WE GENERATE A RECOGNITION AGENT??

A comercial error has released two isomers to the market, only one of them actually works. CAN WE GENERATE A RECOGNITION AGENT??

I know, some results need  some attention, I know, trust me.

I know, some results need some attention, I know, trust me.

Also, Imatinib is cardiotoxic. We research now the competence between allegedly affected enzymes and the carriers to at least delay the toxic effect.

Also, Imatinib is cardiotoxic. We research now the competence between allegedly affected enzymes and the carriers to at least delay the toxic effect.

Diapositiva26

.

Diapositiva27

.

Thanks to all of these wonderful guys who made all publications possible (and also those who gave the money)

Thanks to all of these wonderful guys who made all publications possible (and also those who gave the money)

(The view from my office in Toluca) Any questions?

(The view from my office in Toluca, Mexico) ANY QUESTIONS? Write it in the comments section!

 

If you made it this far, let me tell you that this is also available at Slideshare.com 🙂

Thanks for reading, commenting and sharing!

New paper in JACS


Well, I only contributed with the theoretical section by doing electronic structure calculations, so it isn’t really a paper we can ascribe to this particular lab, however it is really nice to see my name in JACS along such a prominent researcher as Prof. Chad Mirkin from Northwestern University, in a work closely related to my area of research interest as macrocyclic recognition agents.

In this manuscript, a calix[4]arene is allosterically opened and closed reversibly by coordinating different kinds of ligands to a platinum center linked to the macrocycle. (This approach has been referred to as the weak link approach.) I recently visited Northwestern and had a great time with José Mendez-Arroyo, the first author, who showed me around and opened the possibility for further work between our research groups.

(Ligands: Green = Chloride; Blue = Cyanide)

Closed, semi-open and fully open conformations; selectivity is modulated through cavity size. (Ligands: Green = Chloride; Blue = Cyanide)

Here at UNAM we calculated the interaction energies for the two guests that were successfully inserted into the cavity: N-methyl-pyridinium (Eint = 57.4 kcal/mol) and Pyridine-N-oxide (Eint = +200.0 kcal/mol). Below you can see the electrostatic potential mapped onto the electron density isosurface for one of the adducts. Relative orientation of the hosts within the cavity follows the expected (anti-) alignment of mutual dipole moments. At this level of theory, we could easily be inclined to assert that the most stable interaction is indeed the one from the semi-open compound and that this in turn is due to the fact that host and guest are packed closer together but there is also an orbital issue: Pyridine Oxide is a better electron acceptor than N-Me-pyridinium and when we take a closer look to the (Natural Bonding) orbitals interacting it becomes evident that a closer location does not necessarily yields a stronger interaction when the electron accepting power of the ligand is weaker (which is, in my opinion, both logic and at the same time a bit counterintuitive, yet fascinating, nonetheless).

Electrostatic potential mapped onto the electron density surface of one of the aducts under study

Electrostatic potential mapped onto the electron density surface of one of the adducts under study

All calculations were performed at the B97D/LANL2DZ level of theory with the use of Gaussian09 and NBO3.1 as provided within the former. Computing time at UNAM’s supercomputer known as ‘Miztli‘ is fully acknowledged.

The full citation follows:

A Multi-State, Allosterically-Regulated Molecular Receptor With Switchable Selectivity
Jose Mendez-Arroyo Joaquín Barroso-Flores §,Alejo M. Lifschitz Amy A. Sarjeant Charlotte L. Stern , and Chad A. Mirkin *

J. Am. Chem. Soc., Article ASAP
DOI: 10.1021/ja503506a
Publication Date (Web): July 9, 2014

 Thanks to José Mendez-Arroyo for contacting me and giving me the opportunity to collaborate with his research; I’m sure this is the first of many joint projects that will mutually benefit our groups. 

 

New paper in Computational and Theoretical Chemistry


I always get very happy to have a new paper out there! I find it exciting but most of all liberating since it makes you feel like your work is going somewhere but most of all that it is making its way ‘out there’; there is a strong feeling of validation, I guess.

Two very different families of calix[n]arenes (Fig 1) were tested as drug carriers for a very small molecule with a huge potential as a chemotherapeutic agent against Leukemia, namely, 3-phenyl-1H-[1]benzofuro[3,2-c]pyrazole a.k.a. GTP which has proven to be an effective in vitro Tyrosine Kinase III inhibitor. Having such a low molecular weight it is expected to have a very high excretion rate therefore the use of a carrier could increase its retention time and hence its activity. This time we considered n = 4, 5, 6 and 8 for the size of the cavities and R = -SO3H and -OEt as functional groups on the upper rim as to evaluate only a polar coordinating group and a non-polar non-coordinating one since GTP offers two H-bond acceptor sites and one H-bond donor one along the π electron density that could form π – π stacking interactions between the aromatic groups on GTP and the walls of the calixarene.

Fig 1. Calixarenes under study and their complexes with GTP

Fig 1. Calixarenes under study and their complexes with GTP

Once again calculations were carried out at the B97D/6-31G(d,p) level of theory along with molecular dynamics simulations for over 100 ns of production runs. NBO Deletion interaction energies were computed in order to discern which hosts formed the most stable complexes.

NBO Del interaction energies B97D/6-31G(d,p)

NBO Del interaction energies B97D/6-31G(d,p)

You may find a link to the ScienceDirect website for downloading the paper from this link. Last, but certainly not least, I’d like to thank all coauthors for their contributions and patience in getting this study published: Dr. Rodrigo Galindo-Murillo; Alberto Olmedo-Romero; Eduardo Cruz-Flores; Dr. Petronela M. Petrar and Prof. Dr. Kunsági-Máté Sándor. Thanks a lot for everything!

fig8

Donor and acceptor H-bond sites increases the probability of keeping the drug in place for a higher retention rate

Donor and acceptor H-bond sites increases the probability of keeping the drug in place for a higher retention rate

Internal Symposium at CCIQS – 2014 edition


Once again as every year we celebrate our internal symposium here at CCIQS, and like every year, my students presented some of their progress with their research projects. This time, three students, from three different levels, present posters regarding some of the data they’ve obtained.

20140220-221553.jpg

María Eugenia ‘Maru’ Sandoval presented a poster regarding the molecular dynamics simulations performed for the drug Imatinb and a family of calix- and thia-calix[n]arenes as published here and reported in this blog here. ‘Maru’ is now a first year grad student at the National University, UNAM, after spending a year working for a pharmaceutical company. Her research in the realm of photosynthesis has only begun recently, that is why we had to rely on some other data.

20140220-221627.jpg

Luis Enrique Aguilar is researching cation-π interactions within the aromatic cavities of calix[n]arenes in order to find suitable leads among these, our favorite macrocyles, for designing extraction agents of heavy (toxic) metals. Luis Enrique is an undergrad student here at the State University who should finish this year and has shown some interest (threatened us) in writing his dissertation thesis in our research group.

20140220-221638.jpg

Monserrat Enriquez is a PhD student at CINVESTAV under the joint supervision of Dr. Eddie López-Honorato and myself (Dr. Eddie is her principal advisor), her research project involves both theoretical calculations and synthesis of the leads for extraction agents for several Arsenic species. For the time being, Monserrat is here with us, far from her home on the north side of the country, for this semester in which we have to finish with the theoretical section of her work. Besides her research concerning calixarenes she is also running calculations on the interactions between graphene oxide and the aforementioned As species. We are very excited about working with such a complex yet simple material that has such an exciting electronic structure.

This symposium is always interesting and important in bringing our research projects closer to all the comunity of this center. And since symposium comes from the Greek meaning ‘drinking together‘, then lets raise our glasses and toast for the data to come!

Cheers!

20140220-221653.jpg

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.

More interns!


I’ve been neglecting this blog a lot lately! It would seem as little or nothing is going on in our lab but it’s quite the opposite, a lot of good stuff is going on and most of the excitement comes from the results obtained by a few more interns.

20130905-235321.jpg

Eduardo Cruz

20130905-235352.jpg

Alberto Olmedo

Alberto and Eduardo came just as the previous group of interns left. They’re both undergrad students in Pharmaceutical Sciences at Universidad de la Cañada in southern Mexico. My good friend, Dr. María del Carmen Hernández, referred them to me to do a stay during their summer vacations. They are taking where the previous interns (Paulina, Eliana, Javier and Daniel) left and have now obtained the interaction energies for five different host-guest aducts for 3-phenyl-1H-[1]bezofuro[3,2-x]pyrazole, a tyrosine III kinase inhibitor, currently under research for the treatment of leukemia, better known to us as GTP. As before, our molecular carriers are a wide selection of functionalized-calix[n]arenes. These calculations turned out to be rather lengthy; they were all performed at the B97D/6-31+G(d,p) level of theory in order to account for dispersion forces in pi-pi interactions between the aromatic rings in both species.

The third recent addition to our lab is Monserrat Enriquez, who is a PhD student under the supervision of my good friend Dr. Eddie López-Honorato (if you haven’t checked his blog on nuclear energy and materials for nuclear reactions containment go now and follow it; encourage him to post more often!). Monserrat will be co-advised by me. Her project lies within the scope of molecular recognition, materials recovery and bioremediation; calculations and simulations will help the experimental team to point the synthesis of sequestrating agents in the right direction, or, at the very least, to have a better understanding of the forces and interactions lying beneath the formation of such complex structures.

20130905-235410.jpg

Monserrat Enriquez

Last but not least, Luis Enrique is back with a vengeance! He is determined to finish his study on other tyrosine kinase inhibitor drugs. Luis Enrique is an undergrad Chemistry student here in Toluca at the Autonomous Mexico State University, so he will come on his spare time and work from home every now and then; who knows! maybe he’ll end up with a dissertation by the time he finishes his undergrad studies!

But I’m to be left alone pretty soon, as Alberto and Eduardo will stay for a couple of weeks more and Luis Enrique will be here on his spare time. Monserrat will leave on Friday back to Saltillo in Northern Mexico to continue working on the experimental part of her research while working on her calculations from a distance.

Thanks to them for their invaluable help in the development of our research group, for their enthusiasm and hard work. You are now a part of this lab and its doors will always welcome you back!

%d bloggers like this: