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.

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.

Calixarenes offer a more chemically-tunable alternative.

We decided to go with drugs for the treatment of chronic myeloid leukemia

.

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.

GTP was a small place to start (chemical space blocked due to animation lost in translation)

Interaction energies obtained

Hydrogen bonds and pi – pi interactions account for the large interaction energies

Detail of the interactions in some of the obtained geometries

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)

Chemical space increased regard to the one used with GTP.

In both cases, two insertion modes were considered.

Some results…

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.

Where do we go from here?

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??

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.

.

.

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, Mexico) ANY QUESTIONS? Write it in the comments section!