Drugging protein-protein interaction interface with natural products: A computational approach

Abstract

Protein-protein interaction (PPI) process plays an essential role in regulating biological processes inside the cell. Malfunctioning in protein-protein interaction network is responsible for many critical human diseases like cancer and neurodegeneration. Hence, PPI has emerged as an attractive drug target. However, targeting the large area of the PPI interface (~1000-2000) with small molecules which have smaller surface area (~300-500) in comparison to PPI interface is a real challenge in medicinal chemistry. Research suggests that a few amino acid residues residing in the PPI interface have higher involvement in binding of the proteins than other residues, known as hot-spot residues. Targeting hot-spot residues with small molecules has proven to be effective in disrupting PPIs. Natural products and their related moieties historically have been productive sources of lead for drug discovery and development. The chapter discusses computational techniques in detail, such as in silico alanine scanning for hot-spot residue determination in the PPI interface. We also lay insights into the tools and techniques of structure-based drug designing.