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Molecules
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Small Molecules Modulation in Protein-Protein Interactions
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Small Molecules Modulation in Protein-Protein Interactions

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 April 2016) | Viewed by 11526

Special Issue Editor

Dr. Philippe Roche

E-Mail Website
Guest Editor
Laboratory of integrative Structural and Chemical Biology (iSCB), Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS UMR 7258, INSERM U 1068, Institut Paoli-Calmettes, and Aix-Marseille Universités, 13009 Marseille, France
Interests: protein-protein interactions (PPI); small-molecule modulators; structural database dedicated to PPI; druggability of PPI; design of focused libraries dedicated to PPI; in silico drug design; virtual screening; cheminformatics; molecular modeling; molecular dynamics

Special Issue Information

Dear Colleagues,

Due to the implication of protein-protein interactions (PPI) in numerous diseases, among them, cancer, the design of small molecule compounds that are able to modulate (i.e., inhibit or stabilize) protein networks has recently emerged as attractive strategies in drug-discovery campaigns in both academic and private research. In addition, such compounds represent useful chemical probes for studying the molecular basis of the biological processes involved in human diseases. The number of success stories concerning the development of PPI inhibitors has consequently grown over the last decade, including compounds advancing to preclinical and clinical trials, up to phase III. However, despite these encouraging results, in silico design of PPI modulators still remains challenging.

This Special Issue focuses on the design of PPI modulators, their physical, structural, and pharmacokinetic properties, and on the conception of PPI-focused chemical libraries.

Dr. Philippe Roche
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • PPI modulators
  • small molecule
  • natural products
  • macrocycles
  • peptidomimetics
  • fragments
  • PPI-focused chemical libraries
  • diversity oriented synthesis
  • chemical space
  • ADME-Tox properties

Published Papers (2 papers)

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Research

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1829 KiB  
Article
Comparative Analysis of Virtual Screening Approaches in the Search for Novel EphA2 Receptor Antagonists
by Donatella Callegari, Daniele Pala, Laura Scalvini, Massimiliano Tognolini, Matteo Incerti, Silvia Rivara, Marco Mor and Alessio Lodola
Molecules 2015, 20(9), 17132-17151; https://doi.org/10.3390/molecules200917132 - 17 Sep 2015
Cited by 5 | Viewed by 5478
Abstract
The EphA2 receptor and its ephrin-A1 ligand form a key cell communication system, which has been found overexpressed in many cancer types and involved in tumor growth. Recent medicinal chemistry efforts have identified bile acid derivatives as low micromolar binders of the EphA2 [...] Read more.
The EphA2 receptor and its ephrin-A1 ligand form a key cell communication system, which has been found overexpressed in many cancer types and involved in tumor growth. Recent medicinal chemistry efforts have identified bile acid derivatives as low micromolar binders of the EphA2 receptor. However, these compounds suffer from poor physicochemical properties, hampering their use in vivo. The identification of compounds able to disrupt the EphA2-ephrin-A1 complex lacking the bile acid scaffold may lead to new pharmacological tools suitable for in vivo studies. To identify the most promising virtual screening (VS) protocol aimed at finding novel EphA2 antagonists, we investigated the ability of both ligand-based and structure-based approaches to retrieve known EphA2 antagonists from libraries of decoys with similar molecular properties. While ligand-based VSs were conducted using UniPR129 and ephrin-A1 ligand as reference structures, structure-based VSs were performed with Glide, using the X-ray structure of the EphA2 receptor/ephrin-A1 complex. A comparison of enrichment factors showed that ligand-based approaches outperformed the structure-based ones, suggesting ligand-based methods using the G-H loop of ephrin-A1 ligand as template as the most promising protocols to search for novel EphA2 antagonists. Full article
(This article belongs to the Special Issue Small Molecules Modulation in Protein-Protein Interactions)
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Review

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667 KiB  
Review
Small Molecule Targeting of Protein–Protein Interactions through Allosteric Modulation of Dynamics
by Benjamin P. Cossins and Alastair D. G. Lawson
Molecules 2015, 20(9), 16435-16445; https://doi.org/10.3390/molecules200916435 - 10 Sep 2015
Cited by 20 | Viewed by 5788
Abstract
The protein–protein interaction (PPI) target class is particularly challenging, but offers potential for “first in class” therapies. Most known PPI small molecules are orthosteric inhibitors but many PPI sites may be fundamentally intractable to this approach. One potential alternative is to consider more [...] Read more.
The protein–protein interaction (PPI) target class is particularly challenging, but offers potential for “first in class” therapies. Most known PPI small molecules are orthosteric inhibitors but many PPI sites may be fundamentally intractable to this approach. One potential alternative is to consider more attractive, remote small molecule pockets; however, on the whole, allostery is poorly understood and difficult to discover and develop. Here we review the literature in order to understand the basis for allostery, especially as it can apply to PPIs. We suggest that the upfront generation of sophisticated and experimentally validated dynamic models of target proteins can aid in target choice and strategy for allosteric intervention to produce the required functional effect. Full article
(This article belongs to the Special Issue Small Molecules Modulation in Protein-Protein Interactions)
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