Category Archives: Alumni

A New Gradúate Student. Raúl Márquez


We’re always happy at the lab when a student defends their dissertation thesis and now it was the turn of Raúl Márquez-Avilés to do so with flying colors.

The title of his dissertation is “Molecular Dynamics Simulations of 5 potential entry inhibitors for HIV-1“. He performed 500 ns long molecular dynamics simulations of the CD4 – gp 120 proteins interacting with one or several molecules of various lead compounds with inhibitory properties. The leads were obtained previously in our group (by Durbis Castillo, now at McGill) from a massive docking library of ca. 16 million compounds, all having a central piperazine core (Fig1)

Figure 1. Lead compounds: Piperazine cores with heterocyclic substitutions.

The protein gp120 is a surface glyco-protein located at the surface of the HIV virus which couples to the CD4 protein on lymphocytes-T, being this the first step in the infection process of a healthy cell; generating inhibitors of this coupling could help stop the infection from spreading systemically. Four systems were devised: (SB) The reference state for which only gp-120 and CD4 were considered, (S2) A single ligand molecule was placed in the Phe43 cavity of gp120 to assess their inhibitory capacity, (S3) the ligand was placed right outside the Phe43 cavity to assess their entry capacity, and (S4) five ligand molecules were placed outside the Phe43 cavity of gp120 to force their entry (Fig2). Their binding energies were calculated using MM-PBSA and although all five ligands show statistically similar results as inhibitors all five exhibit a stronger binding energy than the reference proving their efficacy in preventing the coupling of the virus to the healthy cell. As a bonus, his research on system S4 shed light on the existence of an allosteric site on gp120 that will warrant further research in our group.

Figure 2. Systems for which 500 ns MD simulations were performed.

This work is still pending publication.

Raúl Márquez has always proven to be a hard working person who is also very self-sufficient student, a very cheerful labmate, and, as I just learned yesterday, an avid chess player. I’m sure he has a bright future in whichever endeavor he chooses now. Congratulations Raúl Márquez-Avilés!

Good Luck to Dr. Jacinto Sandoval


We’re sad to begin this year by saying farewell to Dr. Jacinto Sandoval-Lira who held a postdoc position in our lab for two years with a DGAPA – UNAM scholarship, a very competitive and highly sought-after position here in Mexico. Dr. Sandoval will now relocate to the Technological Institute of San Martín Texmelucan in Puebla, Mexico, whose students will be fortunate to have him as a tutor and a teacher of chemistry in the environmental engineering department.

During the past two years we’ve worked together in various projects, mainly the excitonic transference between photosynthetic pigments but also in calculating reaction mechanisms and solving chemical equilibria problems with various computational approaches, but apart from the research Dr. Sandoval was also a co-organizer of the past Meeting on Physical Chemistry, organized a local course on the use of Dens Tool Kit (DTK), as well as our weekly lab seminars and taught various graduate and undergraduate courses on molecular modeling, chemoinformatics and computational chemistry, not too mention all the collaborations he has brought to our lab in the field of organic chemistry of which I regard him as an expert. He really has been a force of nature!

Aside from a brilliant scientist and a hard working one, Jacinto is an exceptional human being and a great friend. His attention to detail, his drive, and his willingness to help others reach their full potential make him an ideal colleague and an ideal professor. I don’t wish you luck, Jacinto, you don’t need it: I wish you success!

Gustavo “Gus” Mondragón M.Sc. – Thesis Defense


We celebrate the successful thesis defense of Gustavo “Gus” Mondragón who has now completed his Masters degree and is now on to getting a PhD in our group. Gustavo has worked on the search for multiexcitonic states and their involvement in the excitonic transference between photosynthetic pigments, specifically between bacteriochlorophyll-d molecules (BChl-d) from the bchQRU chlorosome whose whole structure is shown in the gallery below. To this end, Gustavo has studied and implemented the Restricted Active Space method with double spin flip (RAS-2SF) with the use of QChem5.0, a method that has required the use and understanding of states with high multiplicities. Additionally, Gustavo has investigated the influence of the environment within the chlorosome by performing ONIOM calculations for the spectroscopic properties of a BChl-d dimer, finding albeit qualitatively a batochromic effect, probably an expected result but nonetheless an impressive feat for the level of theory selected.

There’s still a lot of work to do in this line of research and although we’re eager to publish our results in this excitonic transference mechanism we want to be completely sure that we’re taking every possibility into consideration so we don’t incur into any inconsistencies.

Gustavo cultivates many research interests from excited states of these pigments to biochemical processes that require the use of various tools; I’m sure his permanence in our lab will bring lots of interesting results. Congratulations, Gus! Thank you for your hard work.

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!

A New Graduate Student


With pleasure I announce that last week our very own Gustavo “Gus” Mondragón became the fifth undergraduate student from my lab to defend his BSc thesis and it has to be said that he did it admirably so.

Gus has been working with us for about a year now and during this time he not only worked on his thesis calculating excited states for bacteriochlorophyl pigments but also helped us finishing some series of calculations on calix[n]arene complexes of Arsenic (V) acids, which granted him the possibility to apear as a co-author of the manuscript recently published in JIPH. Back in that study he calculated the interaction energies between a family of calix macrocycles and arsenic acid derivatives in order to develop a suitable extracting agent.

For his BSc thesis, Gus reproduced the UV-Vis absorption spectra of bacteriochlorophyll-a pigments found in the Fenna-Matthews-Olson complex of photosynthetic purple bacteria using Time Dependent Density Functional Theory (TD-DFT) with various levels of theory, with PBEPBE yielding the best results among the tried set. These calculations were performed at the crystallographic conformation and at the optimized structure, also, in vacuo results were compared to those in implicit solvent (SMD, MeOH). He will now move towards his masters where he will further continue our research on photosynthesis.

Thank you, Gustavo, for your hard work and your sense of humor. Congratulations on this step and may many more successes come your way.

 

New paper in Tetrahedron #CompChem “Why U don’t React?”


Literature in synthetic chemistry is full of reactions that do occur but very little or no attention is payed to those that do not proceed. The question here is what can we learn from reactions that are not taking place even when our chemical intuition tells us they’re feasible? Is there valuable knowledge that can be acquired by studying the ‘anti-driving force’ that inhibits a reaction? This is the focus of a new manuscript recently published by our research group in Tetrahedron (DOI: 10.1016/j.tet.2016.05.058) which was the basis of Guillermo Caballero’s BSc thesis.

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It is well known in organic chemistry that if a molecular structure has the possibility to be aromatic it can somehow undergo an aromatization process to achieve this more stable state. During some experimental efforts Guillermo Caballero found two compounds that could be easily regarded as non-aromatic tautomers of a substituted pyridine but which were not transformed into the aromatic compound by any means explored; whether by treatment with strong bases, or through thermal or photochemical reaction conditions.

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These results led us to investigate the causes that inhibits these aromatization reactions to occur and here is where computational chemistry took over. As a first approach we proposed two plausible reaction mechanisms for the aromatization process and evaluated them with DFT transition state calculations at the M05-2x/6-31+G(d,p)//B3LYP/6-31+G(d,p) levels of theory. The results showed that despite the aromatic tautomers are indeed more stable than their corresponding non-aromatic ones, a high activation free energy is needed to reach the transition states. Thus, the barrier heights are the first reason why aromatization is being inhibited; there just isn’t enough thermal energy in the environment for the transformation to occur.

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But this is only the proximal cause, we went then to search for the distal causes (i.e. the reasons behind the high energy of the barriers). The second part of the work was then the calculation of the delocalization energies and frontier molecular orbitals for the non-aromatic tautomers at the HF/cc-pVQZ level of theory to get insights for the large barrier heights. The energies showed a strong electron delocalization of the nitrogen’s lone pair to the oxygen atom in the carbonyl group. Such delocalization promoted the formation of an electron corridor formed with frontier and close-to-frontier molecular orbitals, resembling an extended push-pull effect. The hydrogen atoms that could promote the aromatization process are shown to be chemically inaccessible.

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Further calculations for a series of analogous compounds showed that the dimethyl amino moiety plays a crucial role avoiding the aromatization process to occur. When this group was changed for a nitro group, theoretical calculations yielded a decrease in the barrier high, enough for the reaction to proceed. Electronically, the bonding electron corridor is interrupted due to a pull-pull effect that was assessed through the delocalization energies.

The identity of the compounds under study was assessed through 1H, 13C-NMR and 2D NMR experiments HMBC, HMQC so we had to dive head long into experimental techniques to back our calculations.

Maru Sandoval M.Sc. – Our First Graduate Thesis


It is with great pride that I’d like to announce that for the first time we have a Masters Student graduated from this Comp.Chem. lab: María Eugenia “Maru” Sandoval-Salinas has finished her graduate studies and just last Friday defended her thesis admirably earning not only the degree of Masters of Science in Chemistry but doing so with the highest honors given by the National Autonomous University of Mexico.

Maru’s thesis is for many reasons a landmark in this lab not only because it is the first graduate thesis published from our lab but also the first document on our work about the study of Photosynthesis, a long sought after endeavor now closer to publication. It must also be said that Maru came to this lab when she was an undergraduate student five years ago when I just recently joined UNAM as a researcher fresh out of a postdoc stay. After getting her B.Sc. degree and publishing an article in JCTC (DOI: 10.1021/ct4004178) she now is about to publish more papers that I’m sure will be as highly ranked as the previous one. Thus, Maru was a pioneer in our lab giving it a vote of confidence when we had little to nothing to show for; thanks to her hard work and confidence, along with that of the students who have followed her, we managed to succeed as a consolidated research group in the field of computational chemistry.

More specifically, her thesis centered around finding a mechanism for the excitonic transference between pigments (bacteriochlorophyl-a, BChl-a) in the Fenna-Matthews-Olson (FMO) complex, a protein trimer with seven BChl-a molecules in each monomer, located between the antenna complex and the reaction center in green sulfur bacteria. Among the possible mechanisms explored were Förster’s theory, a modification to Marcus’ theory and finally we explored the possibility of Singlet Fission occurring between adjacent molecules with the help of Dr. David Casanova from the Basque Country University where Maru took a short research stay last autumn. Since nature doesn’t conform to any specific mechanism -specially in a complex arrangement such as the FMO- then it could be possible that a combination of the above might also occur but lets just wait for the papers to be published to discuss it. Calculations were performed through the TD-DFT and the C-DFT formalisms using G09 and Q-Chem; comparing experimental data in CH3OH (SMD implicit calculations with the SVWN5 functional) were undertaken previously for selection of the level of theory.

Now, after two original theses written and successfully defended, an article published in JCTC and more in process, at least five posters, a couple of oral presentations and countless hours at her desk, Maru will go pursuit a PhD abroad where I’m sure she will exceed anyone’s expectations with her work, drive, dedication and scientific curiosity. Thank you, Maru, for all your hard work and trust when this lab needed it the most, we wish you the best for you earn it. You will surely be missed.

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.


    

Two more students graduated!


It is with great pleasure that I’d like to announce the thesis defense of Guillermo “Memo” Caballero and Howard Diaz who in past days became the second and third students, respectively, to get their B.Sc. degrees with theses completed at our lab. I want to publicly thank them for their hard work which hasn’t only contributed with a thesis to our library but will soon contribute with research papers to our count.

Guillermo “Memo” Caballero worked on the calculation of a reaction mechanism that cannot happen. He started as a synthetic chemist and when he hit a wall at the lab he thought computational chemistry might help him get synthesis on the right direction. He has proven now that the aromatization process of a substituted glutarimide into the corresponding pyridine can only proceed only if substituents with a very strong electron withdrawing effect are used. For two reaction mechanisms proposed, both of them intramolecular rearrangements and only one of them concerted, the calculated energy barriers to reach for the corresponding transition states (QST2 and QST3 methods used) are higher than a pyrolitic decomposition. Memo found also that the delocalization of the pi electron system and its extent goes a long way into the stabilization of the non-aromatic analogue. At first we wanted to treat this problem as a tautomeric equilibrium but since we cannot observe the aromatic tautomer there is no equilibrium and hence no tautomerism. We are still thinking how to name this correspondence between the two compounds when we submit the corresponding paper. It must be said that Guillermo graduated with the highest honors in a most deserved way.

Howard Diaz worked on the design of molecular blockers for the entrance process of the HIV-1 virus into lymphocytes through the GP120 protein. Six known blockers based on phenyl-indoyl-urea were assessed through docking, the binding site of the GP120 protein was described in terms of the interactions formed with each on these compounds and that served as the basis for what in the end came up to be a 36 compound library of blockers, whose structures were first optimized at the B3LYP/6-31G** level of theory. All the 42 blockers were docked in the binding site of the protein and a thorough conformational search was performed. From this set, lead compounds were selected in terms of their binding energies (first calculated heuristically) and further studied at the Density Functional Theory, B97D/cc-pVTZ in order to study the electronic structure of the blocker when interacting with a selection of residues at the binding site. Interaction energies calculated at the quantum level are consistent with the complex formation but since we had to cut the protein to only a few residues little correlation is found with the first calculation; this is fine and still publishable, I just wish we had a more seamless transition between heuristics and quantum chemical calculations. Wiberg indexes were very low, as consistent with a hydrophobic cavity, and delocalization energies calculated with second order perturbation theory analysis on the Natural Bond Orbitals revealed that the two most important interactions are C-H…π and Cl…π, these two were selected as key parameters in our design of new drugs for preventing the HIV-1 virus to bind lymphocytes-T; now we only need to have them synthesized and tested (anyone interested?).

Thank you guys for all your hard work, it has truly payed off. I’m completely certain that no matter what you do and where you go you will be very successful in your careers and I wish you nothing but the very best. This lab’s doors will always remain open for you.

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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.

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Eduardo Cruz

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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.

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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!

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