Category Archives: JCTC

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.

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