The Tenth q-bio Summer School - Albuquerque: Lecture 16

Creating a Shape-Based Virtual Compound Library

Whelton Miller

Medicinal chemistry, in particular rational drug design, has generated many opportunities and challenges for scientists across all fields. One technique, molecular docking, is a computational procedure that attempts to predict non-covalent binding of small “drug-like” molecules (ligands) to larger macromolecules (receptors) – proteins in this case. The goal of molecular docking is to start with the unbound structures (ligands and receptors) and efficiently “dock” the ligand into the binding pocket of the receptor. This allows for the calculation of binding affinity, which is a measure of the ligand’s ability to non-covalently attach itself to a particular receptor. An underlying principle of molecular docking is that ligands with similar properties, such as lipophilicity or electrostatic potential via chemical similarity (e.g., shape), should have similar chemical or physical behavior with the same receptors. Therefore, the identification of compounds expected to be active against a given target can be justified using shape similarity. This approach can be extended to include other molecular descriptors, such as electrostatic potential. By mining compounds with similar properties, virtual libraries of drug-like molecules can be created with similar properties and screen them rapidly in order to obtain leads for further drug development. Using a combination of rational drug design software, i.e., Shape Signatures and Autodock Vina, a method is shown to develop such a virtual chemical library.