Computational Drug Discovery and Design

Chapter 15

Protein–Protein Docking in Drug Design and Discovery

Agnieszka A. Kaczor, Damian Bartuzi, Tomasz Maciej Ste ̨pniewski,

Dariusz Matosiuk, and Jana Selent

Abstract

Protein–protein interactions (PPIs) are responsible for a number of key physiological processes in the living
cells and underlie the pathomechanism of many diseases. Nowadays, along with the concept of so-called “hot
spots” in protein–protein interactions, which are well-defined interface regions responsible for most of the
binding energy, these interfaces can be targeted with modulators. In order to apply structure-based design
techniques to design PPIs modulators, a three-dimensional structure of protein complex has to be available.
In this context in silico approaches, in particular protein–protein docking, are a valuable complement to
experimental methods for elucidating 3D structure of protein complexes. Protein–protein docking is easy to
use and does not require significant computer resources and time (in contrast to molecular dynamics) and it
results in 3D structure of a protein complex (in contrast to sequence-based methods of predicting binding
interfaces). However, protein–protein docking cannot address all the aspects of protein dynamics, in particu-
lar theglobal conformational changes duringprotein complex formation. Inspite of this fact, protein–protein
docking is widely used to model complexes of water-soluble proteins and less commonly to predict structures
of transmembrane protein assemblies, including dimers and oligomers of G protein-coupled receptors
(GPCRs). In this chapter we review the principles of protein–protein docking, available algorithms and
software and discuss the recent examples, benefits, and drawbacks of protein–protein docking application to
water-soluble proteins, membrane anchoring and transmembrane proteins, including GPCRs.

Key wordsDrug design and discovery, GPCRs, Molecular modeling, Protein–protein docking,

Transmembrane proteins, Water-soluble proteins

1 Introduction

Protein–protein interactions (PPIs) are at the heart of most cellular

processes as they are involved in a number of cellular phenomena

and greatly contribute to the complexity and diversity of living

organisms [1]. The human interactome has been estimated to

cover about 400,000 PPIs [2]. Protein–protein interactions under-

lie the very basics of any aspect of life, including protein regulation

or signal transmission. Malfunctions of such interaction patterns

may result in cancer or immune disorders [1]. Gathering knowl-

edge on interactions of viral or bacterial protein can facilitate the

Mohini Gore and Umesh B. Jagtap (eds.),Computational Drug Discovery and Design, Methods in Molecular Biology, vol. 1762,
https://doi.org/10.1007/978-1-4939-7756-7_15,©Springer Science+Business Media, LLC, part of Springer Nature 2018

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