Implications of Structural Stability for Drug Design

Abstract

The relevance of structural stability in drug design has been shown by the use of DUck in virtual screening campaign, as reported previously. The method provides a fast and easy way to assess hydrogen bond-based structural stability of a complex. However, the cause and consequences of structural stability in molecular recognition remain unknown. DUck still has some limitations and requires previous knowledge about the system to be applied successfully.

GENERAL OBJECTIVE:

The general objective of this work is to deepen the knowledge of the role and origin of structural stability in molecular recognition and extend its applicability in drug design. We wanted to test DUck on a large and diverse set of protein-ligand complexes and apply it in a more general scenario without detailed knowledge about the simulated system.

DETAILED OBJECTIVES:

The specific objectives were the following:

1. Investigate the role of structural stability in biomolecular complexes:

• Perform a large-scale assessment of hydrogen bond based structural stability on a set of highly trustworthy structures of protein- ligand and protein-fragment complexes. • Compare the binding patterns for different classes of proteins

• Investigate how robust hydrogen bonds are organised in complex’s structure. • Draw useful conclusions for drug design.

• Explain the cause of structural stability. 2. Extend the applicability domain of Dynamic Undocking:

• Combine docking with rDock and post-docking evaluation of poses with DUck into binding mode prediction protocol.

• Test the protocol on the set of complexes of proteins with drug-like molecules and fragments.