Plebiotic SL (Madrid, Spain) and Pharmacellion Ltd (Wirral, UK) have completed a research project on the modelling, structural analysis and molecular dynamics of several Pharmacellion compounds designed to inhibit target protein Na K ATPase, a novel cancer target. The study confirms that all six Pharmacellion compounds studied using the Plebiotic “PleMD” platform bind to their target protein, with lead compounds PCLN-202 and PCLN-201 having the highest affinities. These compounds are in preclinical development for prostate and non-small-cell lung cancers.

The sodium-potassium pump, Na K ATPase, is an important enzyme located in the membrane of animal cells. This enzyme is responsible for the active transport of sodium and potassium ions through the cellular membrane. This ion pump is also involved in the development and progression of some types of cancer, so it is an interesting target for cancer therapeutics.

Pharmacellion has designed several compounds as inhibitors of Na K ATPase, with increased affinity with the ion pump and having modifications – relative to other known inhibitors – that are intended to reduce possible side effects.

Using Plebiotic methods, a 3D computer model of the target protein was generated and various gaps in the model were filled using specialised software. 3D structures of six Pharmacellion compounds were then generated and refined using various software tools, before being used in docking simulations with the target model. All six Pharmacellion compounds were found to dock with their target.

The model of Na K ATPase was then inserted into a virtual cell membrane model with the necessary water molecules and sodium, potassium and chloride ions needed for predicting the affinity of the compounds for the target using Plebiotic’s rapid Molecular Dynamics platform, PleMD.

The Molecular Dynamics results from this virtual model demonstrated good binding and affinity for all six Pharmacellion compounds studied, with lead compounds PCLN-202 and PCLN-201 having the highest affinity.

“We are very pleased with the results of this study, which confirm not only the promising characteristics of Pharmacellion’s lead compounds from previous in vitro and in vivo studies, but also the utility, accuracy and speed of the PleMD platform” said Dr Neil Thomas, CEO of Pharmacellion. “We look forward to future collaboration with Plebiotic as their additional preclinical predictive technologies are launched.”

Álvaro López Medrano, CEO of Plebiotic noted, “It has been a really interesting project considering this large and complex nature of the target protein. We are happy to see that the simulations produced by the PleMD platform have confirmed high affinity binding of the Pharmacellion compounds, as predicted by conventional studies.”