Estimated binding energy model based in Quantitative Structure-Activity Relationships (3D QSAR), for the pharmaceutical industry

New and innovative aspects

• Combine Binding Energy (COMBINE) is used to determine the effect of incorporating the dissolvent.
• It is used as a powerful design tool in receptor drugs.
• COMBINE could determine the electrostatic contribution to binding free energy between a ligand (L) and a receptor to form the complex L-R in the presence or in the absence of a dissolvent.

Main advantages of its use

One of the most important competitive advantage is the possibility to predict and evaluate the interaction energy of a new compound with its biological target before its synthesis, as well as the possibility to quantify the structure-activity relations in analogous series.  Equally, it is possible to build, visualize and optimize molecules with pharmacologic potential and to model by homology macromolecular structures which are still not experimentally available.

Specifications

The biological activity of a compound depends greatly on its interaction energy with the receptor and so the accurate estimation of the compound’s interaction energy is really important to predict a priori the activity of novel compounds before their synthesis. Unfortunately, even knowing the structure of the compound, the interaction is difficult to estimate.

To solve problems with series of interrelated compounds, a simpler model of interaction energy and its molecular mechanism can be built. This model called COMBINE (Combine Binding Energy) analysis is mainly based on the 3D QSAR method (Quantitative Structure-Activity Relationships) which uses receptor-ligand complex structures. The receptor-ligand interaction energy is computerized in AMBER molecular modelling programs. Residual contributions were considered with estimations of the electrostatic contribution of the ligands and receptors desolvatation with biological activity, using a continuous method. Due to the regression analysis PLS (Partial Linear Least Squares Regression Analysis) all the energy values relate to the biological activity.

The COMBINE model uses only one orientation with two limitations: 1- the model computes the contribution of each interaction ligand-binding, with its activity, and so 2- when an orientation is used to predict the activity of novel compounds, their biological activity tends to be slightly unpredictable. 

These limitations have a more severe effect when the compounds of the series show structural variations mainly on one side of its structure. Consequently the model recognizes the influence of the activity of the structural changes that takes place in half of the molecules, but does not receive information about the other half. However, as we mentioned before, this kind of ligands can be eliminated in both alternatives and in the equivalent orientations. So, the ligands were considered in both estimations, and the model “learns” the effect of introducing the structural variability in both sides of the link.

The most important in this technology is the possibility of obtaining a model that adequately considers the duality of the interaction potential to check the ligand sensitivity to orientation within the link-receiver zone as well as its capability to predict.

Applications

• Pharmaceutical sector
• Application techniques for the study of the behavior of macromolecules and drug design.