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A new paper on the Weak Link Approach


Chemically actuating a molecule is a very cool thing to do and the Weak Link Approach (WLA) allows us to do precisely that through the reversible coordination of one or various organometallic centers to a longer ligand that opens or closes a macrocyclic cavity. All this leads to an allosteric effect so important in biological instances available in inorganic molecules. Once again, the Mirkin group at Nortwestern University in Evanston, Illinois, has given me the opportunity to contribute with the calculations to the energetic properties of these actuators as well as their electronic properties for their use as molecular scavengers or selective capsules for various purposes such as drug delivery agents.

As in the previous WLA work (full paper), the NBODel procedure was used at the B97D/LANL2DZ level of theory, only this time the macrocycle consisted of two organometallic centers and for the first time the asymmetric opening of the cavity was achieved, as observed by NMR. With the given fragments, all possibilities shown in scheme 1 were obtained. The calculated bond energies for the Pt – S bonds are around 60 – 70 kcal/mol whereas for the Pt – Cl bonds the values are closer to 90 kcal/mol. This allows for a selective opening of the cavity which can then be closed by removing the chlorine atoms with the help of silver salts.

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For the case of complex mixture 4a, 4b, and 4c, the thermochemistry calculations show they are all basically isoenergetic with differences in the thousandths of kcal/mol. The possibilities for the groups in the weakly bonded ligands are enormous; currently, there is work being done about substituting those phenyl rings for calix[4]arenes in order to have a macrucyclic capsule made by macrocylic capusules.

Thanks to Andrea D’Aquino for taking me into her project, for all the stimulating discussions and her great ideas for expanding WLA into new avenues; I’m sure she’ll succeed in surprising us with more possibilities for these allosteric macrocycles.

The full paper is published in Inorganic Chemistry from the ACS (DOI: 10.1021/acs.inorgchem.7b02745). Thanks for reading and -if you made it this far into the post- happy new year!

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A New Graduate Student!


Last Friday we had a new graduate student when our very own Marco Antonio Diaz defended his BSc thesis on the in silico design of drug carriers based on calix[n]arenes. During his thesis he performed around 160 different calculations regarding the interaction energy of our host-guest inclusion complexes, both using the supramolecular method and the NBODel procedure available in NBO3.1 as provided with Gaussian 09. One of the main targets of this work was to assess both methods -with the proper BSSE corrections- in their capabilities for the calculation of interaction energies.

We found that the NBODel method consistently generates interaction energies that are similar to those of the SM method + the BSSE correction (as opposed to SM – BSSE which is the proper correction). Marco and I are still in the process of writing the article so maybe it will be published in early 2018. In this case we’re using calixarenes to deliver three drugs: warfarine, furosemide, phenylbutazone to compite with ocratoxin-A (OTA) for the binding site in Human Serum Albumin (HSA).

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This project is undertaken in collaboration with my good friend Dr. Sándor Kunsági-Máté in Pécsi Tudomanyegyetem in Hungary.

Congratulations to Marco from all of us here at the lab!

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

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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

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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.

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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!

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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