Brief algorithm description

The algorithm is a direct calculation of the ligand structure for a binding site of the biomacromolecule. It proceeds in three steps:

(i) calculation of the electrostatic field of the target;
(ii) calculation of the complementary electrostatic field in the binding site;
(iii) derivation of the ligand structure from that complementary field.

This “direct” calculation is positioned as an alternative to high throughput docking methods and might result in a significant reduction of the lead generation time and costs. More important, it is inherently capable of generation of unique structures that have never been synthesized or found in the Nature.

The primary focus of the algorithm is on the facilitation of the drug development. However, it is fundamentally suitable for any relatively large structure (e.g. polymers, crystals, nanostructures, both organic and inorganic). The presence of a binding “cavity” is also optional. A ligand could be calculated for a “featureless” molecular surface too. This shall relieve the problem of undruggable targets (macromolecules with poorly defined binding sites).

There are two fundamental problems that had to be resolved on the way: i) an exact (computable) description of the molecular complementarity, and ii) the solution of the inverse problem of molecular electrostatics, namely, the calculation of a molecular structure for the given electrostatic field. The target’s electrostatic field is calculated straightforward by solving the Poisson-Boltzmann equation.

The proposed method dwells upon a solid physico-chemical model, therefore it is inherently aimed to produce the ligand structures with the theoretically highest possible affinity for the given binding site. The ultimate goal is to reach the estimated affinities similar to or exceeding that of avidin-biotin binding (10⁻¹⁴M). This would provide wide margin for further ligand optimization, so that the initial structure could be modified drastically while meeting the expectations for affinity.

Finally, we estimate the affinity of the new ligand to the target macromolecule with one of the available molecular docking packages, or a computational procedure based on COMBINE (COMparative BINding Energy analysis). Currently we are setting up a reliable molecular mechanics protocol, which should provide much better estimations of the binding energy.