Exploring NMR ensembles of calcium binding proteins: Perspectives to design inhibitors of protein-protein interactions

Adriana Isvoran,Constantin T Craescu,Maria A Miteva,Simona Miron,Anne Badel

doi:10.1186/1472-6807-11-24

Abstract

BackgroundDisrupting protein-protein interactions by small organic molecules is nowadays a promising strategy employed to block protein targets involved in different pathologies. However, structural changes occurring at the binding interfaces make difficult drug discovery processes using structure-based drug design/virtual screening approaches. Here we focused on two homologous calcium binding proteins, calmodulin and human centrin 2, involved in different cellular functions via protein-protein interactions, and known to undergo important conformational changes upon ligand binding.ResultsIn order to find suitable protein conformations of calmodulin and centrin for further structure-based drug design/virtual screening, we performed in silico structural/energetic analysis and molecular docking of terphenyl (a mimicking alpha-helical molecule known to inhibit protein-protein interactions of calmodulin) into X-ray and NMR ensembles of calmodulin and centrin. We employed several scoring methods in order to find the best protein conformations. Our results show that docking on NMR structures of calmodulin and centrin can be very helpful to take into account conformational changes occurring at protein-protein interfaces.ConclusionsNMR structures of protein-protein complexes nowadays available could efficiently be exploited for further structure-based drug design/virtual screening processes employed to design small molecule inhibitors of protein-protein interactions.

Highlights

Disrupting protein-protein interactions by small organic molecules is nowadays a promising strategy employed to block protein targets involved in different pathologies
We exploit here docking of 1-naphthyl terphenyl into two homologous Ca2+-binding proteins, CaM and human centrin 2 (HsCen2), to find out the CaM and HsCen2 conformations that could efficiently be employed for further structure-based design of inhibitors of Protein-protein interactions (PPIs)
In this work we performed in silico analysis and docking of 1-naphthyl terphenyl into NMR ensembles of CaM and HsCen2 that revealed a small set of NMR conformations appropriate to perform further structure-based virtual screening for discovering of small PPIs inhibitors

Summary

Introduction

Disrupting protein-protein interactions by small organic molecules is nowadays a promising strategy employed to block protein targets involved in different pathologies. We focused on two homologous calcium binding proteins, calmodulin and human centrin 2, involved in different cellular functions via protein-protein interactions, and known to undergo important conformational changes upon ligand binding. We exploit here docking of 1-naphthyl terphenyl (see Figure 1) into two homologous Ca2+-binding proteins, CaM and human centrin 2 (HsCen2), to find out the CaM and HsCen conformations that could efficiently be employed for further structure-based design of inhibitors of PPIs. CaM and HsCen have a high sequence homology (Figure 2A) and display a structural similarity as both proteins are composed by two EF-hand N- and C-terminal domains connected by a helical linker (see Figure 2B). Following the strong similarity between the two Ca2+-binding proteins we probe in this study a potential terphenyl binding into HsCen

Methods

Results

Conclusion