Category Archives: Drug Delivery
The war against COVID-19 has been waged in many fronts. The computational chemistry community has done their share during this pandemic to put forward a cure, a vaccine, or a better understanding of the molecular mechanisms behind the human infection by the SARS-CoV-2 virus. As few vaccines show currently their heads and start making their way around the globe to stop the spreading, amidst a climate of disinformation, distrust and political upheaval, all of which pose several challenges yet to be faced aside from the technical and scientific ones.
This is by no means a comprehensive review of the literature, in fact, most of the cited literature herein was observed in Twitter under the #CompChem and #COVID combined hashtags; Summarizing the research by the CompChem community on COVID-19 related topics in a single blog-post would be near to impossible—I trust a book is being written on it as I type these lines.
The structural elucidation of the proteins associated to the SARS-CoV-2 virus is probably the first step required in designing chemical compounds capable of modifying their functions and altering their life-cycle without altering the biochemistry of the hosts. The Coronavirus Structural Taskforce has elucidated the structure of 28 proteins of SARS-CoV-2 aside from the 300+ proteins from the previous SARS-CoV virus using the tools from the FoldIt at home game based on the Rosetta program to heuristically predict the structure of these proteins. Structure based drug design rely on the knowledge of the structure of the active site (hence the name), but in the case of newly discovered proteins for which homology modeling is not entirely feasible, a ligand-based approach named D3Similarity was developed early in the pandemic for identifying the possible active sites by the group of Prof. Zhijian Xu. Mapping of the of the viral genome and proteome was also achieved early on during the first dates of lockdown in the American continent. The information was readily made available and usable for further studies which prompts another challenge: the rapid dissemination, review and evaluation of information to make scientifically sound claims and make data-based decisions. In this regard, the role of preprints cannot be stressed enough. Without a rapid communication, scientific results cannot generate a much needed critical mass to turn all these data into knowledge. As evidenced by the vast majority of the links present in this post, ChemRXiv from the ACS served the much needed function to gather, link and put the data for scientific evaluation out there in order to accelerate the discovery of solutions to the various steps of the virus’ reproductive cycle through various strategies.
The role of supercomputing has been paramount worldwide to the various efforts made in CompChem (read the C&EN piece) in various fronts from structural elucidation, such as the AI driven structural modelling of spike proteins and their infection mechanism led by Prof. Rommie Amaro (UCSD) and Dr. Arvind Ramanathan which was celebrated by the Bell Prize, to development of vaccines. Many Molecular Dynamics simulations have been performed on potential inhibitors of proteins such as the spike protein, in some cases these simulations coupled with cryo-EM microscopy allowed for the elucidation of the hinging mechanism of these spike proteins, their thermodynamic properties, and all atoms-simulations assessed the rigidity of the receptor as the cause of its infectivity. Still, owning these computing resources isn’t always cost effective; that’s why there have been outsourced to companies such as Amazon web services as Pearlman did for the QM/DFT calculations of the binding energy of several drug candidates for the inhibition of the virus’ main protease (MPro). Many other CADD studies are available (here, here, and here). Researchers from all around the world can chip in and join the effort by reaching out to the COVID-19 High Performance Computing Consortium (HPC) which brings together some of the most advanced computing systems to the hands of private and academic researchers with relevant projects aimed to the study of the virus. On the other side of the Atlantic, the Partnership for Advanced Computing in Europe (PRACE) also provides access to advanced computing services for research. As an effort to keep all the developing information curated and concentrated, the COVID-19 Molecular Structure and Therapeutics Hub was created to provide a community-driven data repository and curation service for molecular structures, models, therapeutics, and simulations related to computational research related to therapeutic opportunities.
As described above, molecular dynamics simulations are capital in the assessment of how drugs interact with proteins. But molecular dynamics can only do so much as they’re computing intensive so, the use of Polarizable Force Fields (PFF) algorithms to obtain results in the microseconds regime with high-resolution sampling methods which have been applied also to the modeling of the MPro protein; the phase space is sampled by different MD trajectories which are then tested and selected. Aside from classical simulations, artificial intelligence predictions and docking calculations, also quantum mechanical calculations have been employed in the search for the most intimate interactions governing the mechanisms of inhibition of proteins. In this front, a Fragment Molecular Orbital based analysis was carried out to find which residues in MPro interacted the most with a given inhibitor.
Virtual screening is at the heart of the computationally aided drug discovery process, specially high-throughput virtual screening such as the one performed by the group of Andre Fischer at Basel, in which 11 potential drugs were narrowed from a pool of over 600 million compounds that were analyzed as potential protease inhibitors. Repurposing of antiviral drugs, and other entry-inhibiting compounds, is also a major avenue explored in the search for treatments; in the linked study by Shailly Tomar et al. antiviral drugs which are also anti inflammatory are believed to take care of lung inflammation and injury associated to the infection at the same time they tend to disrupt the virus’ infection mechanism. The comeback of Virtual Reality can make virtual screening more cooperative even during lockdown conditions and more ‘tangible’ as the company Nanome has proven with their COVID-19 Town Hall meetings which aim to the modeling of proteins in 3D space. Aside from the de novo and repurposing efforts, the search for peptides against infection by SARS-CoV-2 was an important topic (here and here). More recently, Skariyachan and Gopal turn to natural products from herbal origins for their virtual screening (molecular docking and dynamics). In their perspective the chemical complexity achieved through biosynthesis can overcome the bottleneck of chemical discovery while at the same time turning to the ancient practices of herbal remedies described in Ayurveda. Other researchers like Manish Manish have also turned to libraries of 500,000+ natural compounds to find potential drugs for MPro.
The year is coming to an end but not the pandemic in any way. Now, with the advent of new strains, and the widespread vaccination effort put in place, it is more important than ever to keep the fight strong in our labs but also in our personal habits and responsibilities—the same advices that were given at the beginning of the year are still in effect today and will continue to be for the months to come. I want to wish everyone who reads this a happy holiday season, but above all I want to pay a small tribute to the scientists working relentlessly in one of the largest coordinated scientific efforts in modern history, one that can only be compared to the Moon landing or the Manhattan Project; to those scientists and all the healthcare personnel, may you find rest soon, may your efforts never go unnoticed: Thank you for your service.
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)
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.
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!
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).
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!
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.
So many events going on and so little time to blog about.
Two weeks ago, four members of this group traveled to Morelia in southern Mexico to present their research at the XIII Mexican Physical Chemistry Meeting. The next week after that, they all brought their posters back to Toluca for the internal symposium at CCIQS, where a masters student, María Eugenia, gave a small talk about her research project concerning photosynthesis in bacteria. Below, a short description of their projects is presented in order of seniority.
María Eugenia “Maru” Sandoval
Maru is working in photosynthesis of green sulfur bacteria. Her research deals with the excited states calculations at the Time Dependent DFT level for describing the first stages of photon interaction in antennae complexes of the photosystem II, namely the Fenna-Matthews-Olsen (FMO) complex, which was selected due to its relative structural simplicity over that of more evolved organisms. Maru also gave a talk at the internal Symposium back in Toluca the very next week where she got a positive feedback which will be used in her project.
One of the many strategies out there for treatment of HIV-1 infections is to block those proteins used to anchor the virus to a healthy cell. Sort of getting the virus’ hands busy so they can’t attach to a host. 60+ new compounds derived from thiourea were screened and assessed in their interactions with protein GP120, the protein to which the attachment is made, through docking and DFT calculations. Lead compounds are reported. It must be stressed that Howard got an award at CCIQS for having one of the best posters out of 70 in the entire symposium. Kudos and thanks to you, Howard! We now have some MD simulations in order.
Guillermo “Memo” Caballero
His project has some nice philosophical implications if you ask me. Memo started as an experimental chemist and when he ran into a wall trying to obtain a pyridine from the non-aromatic analogue (glutarimide), he came to our group to run some calculations and find out how to force the aromatization process, or at least rationalize if it could be performed at all. Two mechanisms were proposed and now we know that even when the reaction should be quite exothermic, the reaction barriers are too high to be overcome by conventional methods. We now need to find a way to decrease those barriers (cue transition metal simulations). So in a way we are dealing here with the mechanism of a reaction that never happens (at least in an intramolecular way), leading to a reverse reductio ad absurdum reasoning – we assumed the reaction(s) did happen and we found out why is it impossible for them to happen.
No pic. available as of yet
Luis Enrique “Kike” Aguilar
Luis continues to work with calix(n)arenes, this lab’s first love, in drug delivery systems. He is working with two drugs at once: Bosutinib and Sorafenib, second generation drugs for the treatment of Chronic Myeloid Leukemia in cases were resistance to Imatinib has been developed. One of his main goals is to find a calixarene system which is able to discriminate between Bosutinib and pseudo-bosutinib, a commercial isomer which has incorrectly been available for a few years now.
reers and the advancement of our research group. Now back to work, guys!
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!
If you made it this far, let me tell you that this is also available at Slideshare.com 🙂
Thanks for reading, commenting and sharing!
A couple of weeks ago I was invited to give a talk to a small university in southern Mexico called ‘Universidad de la Cañada‘ in the state of Oaxaca, one of the most underprivileged states in our nation. This institution is a rather small one but the work they are doing over there with as little resources as they have is truly remarkable . UNCA offers degrees in pharmacy, pharmacology, food sciences, clinical chemistry and other topics that aim to supply the needed human resources for the various industries that are settled in the region. There is a true feeling of togetherness at UNCA since they have little pieces of equipment yet they are all fully shared among researchers regardless of who received the finance to acquire them. Last year, two of their students came for a two months stay, after which, Alberto and Eduardo got their names on a publication of our research group. It was nice to see them again and even nicer to learn they are about to finish their studies and that they will come back again to our lab in late July.
Every year at UNCA there is a Pharmacology Day on which the students show the results to their research projects during a poster session and listen to lectures by guest speakers from various universities around Mexico. Most of their projects were aimed to the isolation of natural products from local resources and their usage in several kinds of consumer products. UNCA is in a very small town, village I might say, surrounded by mountains and vegetation; the view was spectacular as you may see from the pictures below. Thank you very much to my good friend Dr. Carmen Hernández-Galindo for inviting me to participate and share our work with their students, I hope we may go back again and keep a fruitful exchange between our groups.
During this talk, I took the opportunity to talk about the aforementioned paper in the context of molecular recognition and their in silico design but I think I should have talked more about the computational strategies that are most employed in the pharmaceutical industry. Never mind. I hope I get the opportunity to right this wrong. Still it was nice to give Alberto and Eduardo the opportunity to brag a little about being published authors.
Kudos to Rola Aburto, Dr. Margarita Bernabé, Dr. Rocío Rosas, and all the academic staff at UNCA for their invaluable dedication to teaching science against all odds, I can testify, through the hard work of their students, hat their effort is paying off.
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-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.
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.
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!
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.
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.
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.