Protein Interface Pharmacophore Mapping Tools for Small Molecule Protein: Protein Interaction Inhibitor Discovery

Voet, Arnout; Banwell, Eleanor F.; Sahu, Kamlesh Kumar; Heddle, Jonathan G.; Zhang, Kam Y. J.

doi:10.2174/1568026611313090003

Cited by 33 publications

(23 citation statements)

References 106 publications

(95 reference statements)

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“…It has been challenging to effectively disrupt RGS4/Gα and other protein-protein interactions, especially in the CNS, but progress is being made (17)(18)(19) . Indeed, the emerging consensus in the field is that effective inhibitors of protein-protein interactions (iPPIs) may not meet the "standard" pharmaceutical criteria for drug-like molecules (20,21) .…”

mentioning

confidence: 99%

Selectivity and Anti-Parkinson’s Potential of Thiadiazolidinone RGS4 Inhibitors

Blazer

Storaska

Jutkiewicz

et al. 2015

ACS Chem. Neurosci.

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Many current therapies target G protein coupled receptors (GPCR), transporters, or ion channels. In addition to directly targeting these proteins, disrupting the protein-protein interactions that localize or regulate their function could enhance selectivity and provide unique pharmacologic actions. Regulators of G protein signaling (RGS) proteins, especially RGS4, play significant roles in epilepsy and Parkinson's disease. Thiadiazolidinone (TDZD) inhibitors of RGS4 are nanomolar potency blockers of the biochemical actions of RGS4 in vitro. Here, we demonstrate the substantial selectivity (8- to >5000-fold) of CCG-203769 for RGS4 over other RGS proteins. It is also 300-fold selective for RGS4 over GSK-3β, another target of this class of chemical scaffolds. It does not inhibit the cysteine protease papain at 100 μM. CCG-203769 enhances Gαq-dependent cellular Ca(2+) signaling in an RGS4-dependent manner. TDZD inhibitors also enhance Gαi-dependent δ-OR inhibition of cAMP production in SH-SY-5Y cells, which express endogenous receptors and RGS4. Importantly, CCG-203769 potentiates the known RGS4 mechanism of Gαi-dependent muscarinic bradycardia in vivo. Furthermore, it reverses raclopride-induced akinesia and bradykinesia in mice, a model of some aspects of the movement disorder in Parkinson's disease. A broad assessment of compound effects revealed minimal off-target effects at concentrations necessary for cellular RGS4 inhibition. These results expand our understanding of the mechanism and specificity of TDZD RGS inhibitors and support the potential for therapeutic targeting of RGS proteins in Parkinson's disease and other neural disorders.

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mentioning

confidence: 99%

Selectivity and Anti-Parkinson’s Potential of Thiadiazolidinone RGS4 Inhibitors

Blazer

Storaska

Jutkiewicz

et al. 2015

ACS Chem. Neurosci.

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“…Identification of the putative binding sites is often the first step in assessing target druggability, and has important implications for structure‐based drug design . In this study, we have performed MD simulations on active and inactive PhoP RDs (dimeric and monomeric), followed by binding free energy calculations, a quantitative hot‐spot analysis, and pocket‐detecting screenings, to assess the druggability of this protein.…”

Section: Discussionmentioning

confidence: 99%

Computational Studies of the Active and Inactive Regulatory Domains of Response Regulator PhoP Using Molecular Dynamics Simulations

Qing

Steenackers

Venken

et al. 2017

Molecular Informatics

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The response regulator PhoP is part of the PhoP/PhoQ two-component system, which is responsible for regulating the expression of multiple genes involved in controlling virulence, biofilm formation, and resistance to antimicrobial peptides. Therefore, modulating the transcriptional function of the PhoP protein is a promising strategy for developing new antimicrobial agents. There is evidence suggesting that phosphorylation-mediated dimerization in the regulatory domain of PhoP is essential for its transcriptional function. Disruption or stabilization of protein-protein interactions at the dimerization interface may inhibit or enhance the expression of PhoP-dependent genes. In this study, we performed molecular dynamics simulations on the active and inactive dimers and monomers of the PhoP regulatory domains, followed by pocket-detecting screenings and a quantitative hot-spot analysis in order to assess the druggability of the protein. Consistent with prior hypothesis, the calculation of the binding free energy shows that phosphorylation enhances dimerization of PhoP. Furthermore, we have identified two different putative binding sites at the dimerization active site (the α4-β5-α5 face) with energetic "hot-spot" areas, which could be used to search for modulators of protein-protein interactions. This study delivers insight into the dynamics and druggability of the dimerization interface of the PhoP regulatory domain, and may serve as a basis for the rational identification of new antimicrobial drugs.

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“…Recent advances in the discovery of small molecule proteinprotein interaction inhibitors (SMPPIIs) have made the modulation of protein-protein interactions (PPIs) achievable [160][161][162][163][164]. VS approaches have played a significant role in changing the notion about the undruggability of PPIs.…”

Section: Hlvs For the Identification Of Smppiismentioning

confidence: 99%

Hierarchical virtual screening approaches in small molecule drug discovery

Kumar¹,

Zhang²

2015

Methods

135

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Virtual screening has played a significant role in the discovery of small molecule inhibitors of therapeutic targets in last two decades. Various ligand and structure-based virtual screening approaches are employed to identify small molecule ligands for proteins of interest. These approaches are often combined in either hierarchical or parallel manner to take advantage of the strength and avoid the limitations associated with individual methods. Hierarchical combination of ligand and structure-based virtual screening approaches has received noteworthy success in numerous drug discovery campaigns. In hierarchical virtual screening, several filters using ligand and structure-based approaches are sequentially applied to reduce a large screening library to a number small enough for experimental testing. In this review, we focus on different hierarchical virtual screening strategies and their application in the discovery of small molecule modulators of important drug targets. Several virtual screening studies are discussed to demonstrate the successful application of hierarchical virtual screening in small molecule drug discovery.

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Protein Interface Pharmacophore Mapping Tools for Small Molecule Protein: Protein Interaction Inhibitor Discovery

Cited by 33 publications

References 106 publications

Selectivity and Anti-Parkinson’s Potential of Thiadiazolidinone RGS4 Inhibitors

Selectivity and Anti-Parkinson’s Potential of Thiadiazolidinone RGS4 Inhibitors

Computational Studies of the Active and Inactive Regulatory Domains of Response Regulator PhoP Using Molecular Dynamics Simulations

Hierarchical virtual screening approaches in small molecule drug discovery

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