Abstract
Current computational methods have not been able to discover an unknown binding site for low-molecular ligands on a protein receptor and predict parameters of their interaction when this binding site is not distinguished by energy of binding or structural features. Authors propose a method to find an unknown, structurally undefined site for binding low-molecular inhibitors with a protein, as well as to predict kinetic parameters for new compounds using x-ray structure of a protein receptor and experimental interaction constants of a training set of inhibitors. The developed method is applied to discover structural and kinetic parameters of binding C1q, a protein from the first component of complement system, to low-molecular ligands that inhibit its interactions with immune complexes. Authors have suggested that these ligands bind to a region of C1q globular head near residues Arg150 of chain B, and Lys160 and His67 of chain C, supposedly inhibiting the classical pathway of complement activation. Ligands that inhibit interaction of C1q with immune complexes can be used in the therapy of pathological conditions that are related to unwanted complement activation: allergic reactions, xenograft rejection, etc.
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