Monthly Archives: January 2018

Our first dabble in #MedChem through #CompChem

We’ve expanded the scope of our research interests from quantum mechanical calculations to docking and MedChem for over a year now; it has been a very interesting ride and a very rich avenue of research to explore. Durbis Castillo has led -out of his own initiative- this project and today he presents us with a guest post on the nuances of his project. Bear in mind that the detail of the calculations and a small -very targeted- tutorial on MAESTRO will be provided later in further posts and that making all this decisions required a long process of trial and error, we can only thank Dr. Antonio Romo for his help in minimizing the time this process took.

HIV is a tricky virus, and even though many of the steps included in its lifecycle are druggable, the chemical machinery making it work has been quite elusive since research groups started studying it. Highly Active Antiretroviral Therapy (HAART) works thanks to the combination of several drugs targeting different proteins such as the HIV protease or reverse transcriptase.

In 1998 the elucidation of the gp120 envelope glycoprotein crystal structure introduced a new step in the drug discovery race: HIV entry. Since drugs targeting gp120 have not been widely explored or developed, we decided to use common methodologies like docking (rigid and fit-induced) and ADME predictions to address the following question: How can we easily discover a molecule that inhibits gp120 binding to the lymphocyte CD4 receptor without having to synthesize it first? The answer was to perform a virtual screening with a bottleneck methodology based on docking calculations.

Docking methodologies are often looked as insufficient, careless or even unscientific, since the algorithms they are founded upon are not as accurate or descriptive as the ones that support DFT or ab initio calculations, for example. But there is a huge advantage to simpler operations: less computational resources are required. Then, following Russia’s example when making tanks during the WWII, why not make thousands or millions of docking calculations to quickly explore an entire chemical space and find which molecules are more likely to bind the protein?

And this is exactly what we did. We built a piperazine-based dataset of 16.3 million compounds, all of them including fragments that are reported in the medicinal chemistry literature, thus having two main characteristics, synthetic accessibility and pharmacological activity. These 16.3 million compounds were thoroughly filtered through several docking steps, each one of them being more accurate and comprehensive than the previous one, abruptly eliminating poorly fitted molecules, leaving us with a total of 275 candidates that were redocked in a different crystal structure and a different program (consensus docking).

After analyzing the ADME properties of the candidates, with descriptors such as human oral absorption and possible metabolic reactions, as well as the Induced-Fit Docking score of these molecules, ten ligands were selected as the best ones inside the analyzed chemical space. You can see ligand 255 (figure 1) as an example of the molecules that obtained the best scores throughout the docking steps.


Figure 1

Many of the colleague researchers related to this kind of topics asked “Why didn’t you download a set of molecules from Zinc or Maybridge?” And the answer to this question includes three aspects: first we wanted to test a combinatorial approach to drug design, second, we wanted to test whether including a piperazine as the core of the set of molecules would immediately grant them activity and high potency, and finally, a built database will always confer a higher degree of novelty to the possible hits when compared to commercially available compounds whose synthesis has already been developed. However, this last point needs to be addressed by an organic chemist since none of the molecules from our database have ever been synthesized (any takers?).

Right now, we are trying to explore further through molecular dynamics simulations using Desmond and Amber. Other future goals for this project include screening large databases of commercial and novel compounds with gp120 and other proteins involved in the HIV lifecycle. Also, we remain open to collaborate with anyone interested in taking the challenge to synthesize our molecules, as well as performing the biochemical assays to get an idea of their activity.

More details on MD simulations and the path of our first virtual hits to follow. Anyone interested in reading my thesis work can contact me through my linkedin profile at An article is under preparation and will soon be submitted, stay tuned!


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.


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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