Metadynamics for Perspective Drug Design: Computationally Driven Synthesis of New Protein–Protein Interaction Inhibitors Targeting the EphA2 Receptor

Incerti, Matteo; Russo, Simonetta; Callegari, Donatella; Pala, Daniele; Giorgio, Carmine; Zanotti, Ilaria; Barocelli, Elisabetta; Vicini, Paola; Vacondio, Federica; Rivara, Silvia; Castelli, Riccardo; Tognolini, Massimiliano; Lodola, Alessio

doi:10.1021/acs.jmedchem.6b01642

Cited by 32 publications

(53 citation statements)

References 52 publications

(96 reference statements)

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“…The metadynamics method has been successfully applied to study many biophysical problems including computational drug design. [60][61][62][63][64][65][66] In this work, we used an eigenvector as a CV 67…”

Section: Metadynamics Simulationsmentioning

confidence: 99%

Interplay of cysteine exposure and global protein dynamics in small‐molecule recognition by a regulator of G‐protein signaling protein

et al. 2018

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Regulator of G protein signaling (RGS) proteins play a pivotal role in regulation of G proteincoupled receptor (GPCR) signaling and are therefore becoming an increasingly important therapeutic target. Recently discovered thiadiazolidinone (TDZD) compounds that target cysteine residues have shown different levels of specificities and potencies for the RGS4 protein, thereby suggesting intrinsic differences in dynamics of this protein upon binding of these compounds. In this work, we investigated using atomistic molecular dynamics (MD) simulations the effect of binding of several small-molecule inhibitors on perturbations and dynamical motions in RGS4.Specifically, we studied two conformational models of RGS4 in which a buried cysteine residue is solvent-exposed due to side-chain motions or due to flexibility in neighboring helices. We found that TDZD compounds with aromatic functional groups perturb the RGS4 structure more than compounds with aliphatic functional groups. Moreover, small-molecules with aromatic functional groups but lacking sulfur atoms only transiently reside within the protein and spontaneously dissociate to the solvent. We further measured inhibitory effects of TDZD compounds using a protein-protein interaction assay on a single-cysteine RGS4 protein showing trends in potencies of compounds consistent with our simulation studies. Thermodynamic analyses of RGS4 conformations in the apo-state and on binding to TDZD compounds revealed links between both conformational models of RGS4. The exposure of cysteine side-chains appears to facilitate initial binding of TDZD compounds followed by migration of the compound into a bundle of four helices, thereby causing allosteric perturbations in the RGS/Gα protein-protein interface. K E Y W O R D S allosteric inhibitors, drug discovery, molecular dynamics, protein-protein interactions, regulators of G-protein signaling, Thiadiazolidinone inhibitors

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Section: Metadynamics Simulationsmentioning

confidence: 99%

Interplay of cysteine exposure and global protein dynamics in small‐molecule recognition by a regulator of G‐protein signaling protein

et al. 2018

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“…In this respect, much has achieved in terms of free‐energy perturbation (FEP) calculations . We are confident that efficient and easy‐to‐prepare protocols and set‐ups for methods like steered‐MD and metadynamics will soon undergo similar improvements for prospective drug design . This will further open up these methods to computational medicinal chemistry.…”

Section: Improved Sampling Of Configuration Space Through Dynamic Docmentioning

confidence: 99%

“…From the first application of metadynamics to small molecule binding studies, we have now seen prospective applications of this method to estimate the binding affinity of compounds. These compounds have then been prioritized accordingly for synthesis and experimental tests during drug discovery projects …”

Section: Path‐based Versus Alchemical Transformations In Dynamic Dockingmentioning

confidence: 99%

Recent advances in dynamic docking for drug discovery

Vivo

Cavalli

2017

WIREs Comput Mol Sci

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Molecular docking allows the evaluation of ligand‐target complementarity. This is the crucial first step in small‐molecule drug discovery. Over the last decade, increasing computer power and more efficient molecular dynamics (MD) software have prompted the use of MD for molecular docking. The resulting dynamic docking offers major improvements by (1) taking full account of the structural flexibility of the drug‐target system and (2) allowing the computation of the free energy and kinetics associated with drug binding. Here, we examine the recent advances in dynamic docking, while also considering the challenges and limitations that this powerful approach must overcome to impact fast‐paced drug discovery. WIREs Comput Mol Sci 2017, 7:e1320. doi: 10.1002/wcms.1320 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Mechanics Software > Molecular Modeling

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“…Metadynamics has been popularly used in many drug discovery applications . Examples include the study of protein‐ligand binding and unbinding mechanisms, which lead to major conformational changes in the proteins.…”

Section: Metadynamics: a ‘Piling‐of‐hills’ Approachmentioning

confidence: 99%

Molecular ‘time‐machines’ to unravel key biological events for drug design

Coote

Barakat

2017

WIREs Comput Mol Sci

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Molecular dynamics (MD) has become a routine tool in structural biology and structure-based drug design (SBDD). MD offers extraordinary insights into the structures and dynamics of biological systems. With the current capabilities of high-performance supercomputers, it is now possible to perform MD simulations of systems as large as millions of atoms and for several nanoseconds timescale. Nevertheless, many complicated molecular mechanisms, including ligand binding/unbinding and protein folding, usually take place on timescales of several microseconds to milliseconds, which are beyond the practical limits of standard MD simulations. Such issues with traditional MD approaches can be effectively tackled with new generation MD methods, such as enhanced sampling MD approaches and coarse-grained MD (CG-MD) scheme. The former employ a bias to steer the simulations and reveal biological events that are usually very slow, while the latter groups atoms as interaction beads, thereby reducing the system size and facilitating longer MD simulations that can witness large conformational changes in biological systems. In this review, we outline many of such advanced MD methods, and discuss how their applications are providing significant insights into important biological processes, particularly those relevant to drug design and discovery.FIGURE 1 | A schematic representation of a metadynamics protocol. The figure shows that a mock system (in yellow color) is initially trapped in a local minimum. During metadynamics, the Gaussian potentials (Gaussians shown in blue) are added to the energy wells, such that the system reaches the first saddle point only to fall into the next energy well. This process is iterated until all possible energetic wells are filled with Gaussians, thus leading to a flat energy surface. Overview

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Metadynamics for Perspective Drug Design: Computationally Driven Synthesis of New Protein–Protein Interaction Inhibitors Targeting the EphA2 Receptor

Cited by 32 publications

References 52 publications

Interplay of cysteine exposure and global protein dynamics in small‐molecule recognition by a regulator of G‐protein signaling protein

Interplay of cysteine exposure and global protein dynamics in small‐molecule recognition by a regulator of G‐protein signaling protein

Recent advances in dynamic docking for drug discovery

Molecular ‘time‐machines’ to unravel key biological events for drug design

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