Abstract
Molecular recognition is one of the key principles in the development of
active pharmaceutical compounds. Active molecules that can be delivered in vivo to a
biological target, responsible for pathological states associated with a disease, can be
developed into therapeutic agents. Such molecules must overcome relevant biological
barriers and establish intermolecular interactions with the target in order to modulate its
activity. The drug discovery process entails the identification of potential therapeutic
agents and the design of optimal formulations for targeted or prolonged drug release in
vivo. This requires a balanced and dynamic interplay of interactions between the
therapeutic agent and different molecular systems through diverse environments.
Computational methods, including molecular dynamics simulation, complement
experiments in the evaluation of relevant biochemical processes at different stages of
drug development, e.g., the elucidation of the ligand mode of action. In this chapter, we
will explore the applications of various molecular modeling approaches to evaluate the
key interactions small molecules form with different targets. Molecular docking is the
most common tool used to evaluate the ligand complementarity to the target binding
site. Although the flexible receptor and induced fit approaches provide some additional
insights into how target flexibility affects ligand binding, biomolecules have a large
number of degrees of freedom, often demanding the use of more exhaustive sampling
methods to explore the ligand-binding associated conformational dynamics. This can
be achieved with molecular dynamics and enhanced sampling approaches to model
large conformational changes. In particular, molecular dynamics of protein-ligand
complexes can describe the plasticity of the protein binding sites by identifying
dynamic pharmacophores―dynophores. These pharmacophore models incorporate
information on target flexibility and describe the dynamics of intermolecular
interactions. We will provide a relevant introduction to the above-mentioned
techniques and explore key successful applications in hit discovery and lead
optimization efforts of drug development campaigns.