A Novel analog approach for fast evaluation of affinity between ligand and receptor in scaled up molecular models

Abstract

AbstractRational structure based drug design aims at identifying ligand molecules that bind to the active site of a target molecule with high affinity (low binding free energy), to promote or inhibit certain biofunctions. Thus, it is absolutely essential that one can evaluate such affinity for the predicted molecular complexes in order to design drugs effectively. A key observation is that, binding affinity is proportional to the geometric fit between the two molecules. Having a way to assess the quality of the fit enables one to rank the quality of potential drug solutions. Other than experimental methods that are associated with excessive time, labor and cost, several in silico methods have been developed in this regard. However, a main challenge of any computation-based method is that, no matter how efficient the technique is, the trade-off between accuracy and speed is inevitable. Therefore, given today’s existing computational power, one or both is often compromised. In this paper, we propose a novel analog approach, to address the aforementioned limitation of computation-based algorithms by simply taking advantage of Kirchhoff’s circuit laws. Ligand and receptor are represented with 3D printed molecular models that account for the flexibility of the ligand. Upon the contact between the ligand and the receptor, an electrical current will be produced that is proportional to the number of representative contact points between the two scaled up molecular models. The affinity between the two molecules is then assessed by identifying the number of representative contact points obtainable from the measured total electrical current. The simple yet accurate proposed technique, in combination with our previously developed model, Assemble-And-Match, can be a breakthrough in development of tools for drug design. Furthermore, the proposed technique can be more broadly practiced in any application that involves assessing the quality of geometric match between two physical objects.