Abstract
Investigating protein-protein interactions (PPIs) holds great potential for therapeutic applications, since they mediate intricate cell signaling networks in physiological and disease states. However, their complex and multifaceted nature poses a major challenge for biochemistry and medicinal chemistry, thereby limiting the druggability of biological partners participating in PPIs. Molecular Dynamics (MD) provides a solid framework to study the reciprocal shaping of proteins’ interacting surfaces. Here, we review successful applications of MD-based methods developed in our group to predict interfacial areas involved in PPIs of pharmaceutical interest. We report two interesting examples of how structural, dynamic and energetic information can be combined into efficient strategies which, complemented by experiments, can lead to the design of new small molecules with promising activities against cancer and infections. Our advances in targeting key PPIs in angiogenic pathways and antigen-antibody recognition events will be discussed for their role in drug discovery and chemical biology.
Highlights
The existence of complex wirings in protein-protein interaction (PPI) networks finely modulates the inner working of the circuits at the basis of cell life
We report two interesting examples of how structural, dynamic and energetic information can be combined into efficient strategies which, complemented by experiments, can lead to the design of new small molecules with promising activities against cancer and infections
PPIs in angiogenic pathways and antigen-antibody recognition events will be discussed for their role in drug discovery and chemical biology
Summary
The existence of complex wirings in protein-protein interaction (PPI) networks finely modulates the inner working of the circuits at the basis of cell life. HTS of small molecules against biochemically-reconstituted complexes have led to the identification of useful compounds with phenotypic effects when tested in cells In this case, instead of directly monitoring physical interaction, researchers set out to characterize the functional consequences of the inhibition of a particular class of PPIs as a surrogate for binding measurements [9,12]. MD simulations can be integrated with quantum calculations to describe complex reactive processes at the basis of downstream recognition events [20] In this focused perspective, we will discuss cases from our own experience where MD-based approaches have been used to derive compact physico-chemical descriptors of peptide-protein interactions that could be efficaciously translated into the discovery of new active small molecules, and to predict specific types of protein-protein interaction interfaces (namely those involved in antigen-antibody binding). At the end of this paper, we will discuss possible perspectives in the development of novel therapeutics, such as drugs with novel mechanisms and synthetic antigens for vaccination
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