Current Topics in Medicinal Chemistry - Volume 15, Issue 20, 2015

Many key cellular events determining the thin line between healthy and oncogenic behavior rely on the proper functioning of protein-protein interactions (PPIs). Alterations that affect the affinity of a protein-protein binding site may destabilize a desired healthy interaction, or stabilize an oncogenic interaction. The understanding that there are a few key hot-spot residues that are mainly responsible for the binding energy Read More

The majority of functionally important biological processes are regulated by allosteric communication within individual proteins and across protein complexes. The proteins controlling these communication networks respond to changes in the cellular environment by switching between different conformational states. Targeting the interface residues mediating these processes through the rational identification of molecules modul Read More

In recent years the ever so complex field of drug discovery has embraced novel design strategies based on biophysical fragment screening (fragment-based drug design; FBDD) using nuclear magnetic resonance spectroscopy (NMR) and/or structure-guided approaches, most often using X-ray crystallography and computer modeling. Experience from recent years unveiled that these methods are more effective and less p Read More

Proteins are not static objects. To carry out their functions in the cells and participate in biochemical interaction networks, proteins have to explore different conformational substates, which favor the adaptation to different partners and ultimately allow them to respond to changes in the environment. In this paper we discuss the implications of including the atomistic description of protein dynamics and flexibility in the con Read More

Protein-protein interactions (PPI) are at the center of molecular mechanisms of life. The protein ligands convene for regulation of biological function: adding, enhancing or inhibiting activity, for assistance in structural integrity or to enable subsequent PPI. All these general roles of PPI are represented in the proteasome, the giant proteolytic factory universally present in human cells. The proteasome is a renowned target fo Read More

Biological systems rely on the establishment of interactions between biomolecules, which take place in the aqueous environment of the cell. It was already demonstrated that a small set of residues at the interface, Hot-Spots(HS), contributes significantly to the binding free energy. However, these energetic determinants of affinity and specificity are still not fully understood. Moreover, the contribution of water to their HS char Read More

PAR1, member of the family of protease-activated receptors, is a GPCR whose activation requires a proteolytic cleavage at its extracellular N-terminus to unveil a tethered activating ligand. Although thrombin is the main activator of this receptor, diverse other proteases can also activate and disarm PAR1. Besides, tethered activating ligand-based peptides (PAR-APs) can also activate the receptor. PAR1 mainly signals via G Read More