Search for invisible binding sites of low-molecular-weight compounds on protein molecules and prediction of inhibitory activity

Abstract

Current computational methods have not been able to discover an unknown site for low-molecular-weight ligands on a protein receptor and predict parameters of their interaction when the binding site is not distinguished by energy of binding or structural features. The authors propose a method to find an unknown, structurally undefined site for binding low-molecular-weight inhibitors to a protein, as well as to predict kinetic parameters for new compounds using the X-ray structure of a protein receptor and experimental interaction constants of a training set of inhibitors. The developed method was applied to discover the structural and kinetic parameters of the binding between C1q, a protein of the first component of complement system, and low-molecular-weight ligands that inhibit the C1q interaction with immune complexes. Authors suggest that these ligands bind to a region of C1q globular head near residues Arg150 of chain B and Lys160 and His167 of chain C, which supposedly inhibits the classical pathway of complement activation. Ligands that inhibit the interaction of C1q with immune complexes can be used in the therapy of pathological conditions that are related to the activation of unwanted complements, i.e., allergic reactions, xenograft rejection, etc.