Special Issue "Small Molecules Targeting Protein-Protein Interactions (PPIs): Current Strategies for the Development of New Drugs"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 15 November 2022 | Viewed by 2454

Special Issue Editor

Dr. Sachin P. Patil
E-Mail Website
Guest Editor
School of Engineering, Widener University, Chester, PA 19013, USA
Interests: Alzheimer's disease; cancer; coronary heart disease; immune checkpoints; interactome engineering; P53-MDM2 Inhibitors; PD-1/PD-L1 Inhibitors and enhancers; virtual screening; docking, molecular dynamics; machine learning

Special Issue Information

Dear Colleagues,

Protein–Protein Interactions (PPIs) are key cellular effectors regulating and executing the majority of the important biological functions in living organisms, including humans. Accordingly, PPIs represent a vast source of novel therapeutic targets, with the size of the human interactome reaching an estimated number of over 300,000 interactions and counting. This is welcome news in light of the disappointingly well-known decrease in drug discovery and development efficiency over the years, primarily due to the exhaustion of effective targets for traditional drug design that focuses on single proteins as opposed to PPIs.

To date, the Interactome Engineering through PPI modulation has been under the realm of primarily large biotherapeutics including monoclonal antibodies, protein fragments and macrocyclic peptides. The small-molecule tractability of PPIs, however, is on the rise, with the first such small-molecule drugs entering clinical trials recently, providing the much-needed impetus for this traditionally challenging area of research.

The journal Pharmaceuticals aims to highlight successes, challenges and emerging opportunities in this field, with particular emphasis on the various strategies, both experimental and computational, being utilized for the development of small-molecule modulators of clinically relevant PPIs. Both small-molecule inhibitors as well as stabilizers of PPIs are of importance.

We look forward to your contribution.

Dr. Sachin P. Patil
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 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

  • protein–protein interaction (PPIs)
  • PPI modulation
  • PPI inhibitors
  • PPI stabilizers
  • drug discovery and design
  • small molecule drugs

Published Papers (3 papers)

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Research

Article
Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists
Pharmaceuticals 2022, 15(6), 740; https://doi.org/10.3390/ph15060740 - 13 Jun 2022
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Abstract
Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and GLP-1 [...] Read more.
Glucagon-like peptide-1 (GLP-1) is easily degraded by dipeptidyl peptidase-4 (DPP-4) in the human body, limiting its therapeutic effect on type II diabetes. Therefore, improving GLP-1 receptor agonist (GLP-1RA) stability is a major obstacle for drug development. We analyzed human GLP-1, DPP-4, and GLP-1 receptor structures and designed three GLP-1RAs, which were introduced into fusion protein fragments and changed in the overall conformation. This modification effectively prevented GLP-1RAs from entering the DPP-4 active center without affecting GLP-1RAs’ ability to bind to GLP-1R, the new GLP-1RA hypoglycemic effect lasting for >24 h. Through molecular modeling, molecular dynamics calculation, and simulation, possible tertiary structure models of GLP-1RAs were obtained; molecular docking with DPP-4 and GLP-1R showed access to the fusion protein. The overall conformational change of GLP-1RAs prevented DPP-4 binding, without affecting GLP-1RAs’ affinity to GLP-1R. This study provides important drug design ideas for GLP-1RA development and a new example for application of structural biology-based protein design in drug development. Full article
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Article
Machine-Learning Guided Discovery of Bioactive Inhibitors of PD1-PDL1 Interaction
Pharmaceuticals 2022, 15(5), 613; https://doi.org/10.3390/ph15050613 - 16 May 2022
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Abstract
The selective activation of the innate immune system through blockade of immune checkpoint PD1-PDL1 interaction has proven effective against a variety of cancers. In contrast to six antibody therapies approved and several under clinical investigation, the development of small-molecule PD1-PDL1 inhibitors is still [...] Read more.
The selective activation of the innate immune system through blockade of immune checkpoint PD1-PDL1 interaction has proven effective against a variety of cancers. In contrast to six antibody therapies approved and several under clinical investigation, the development of small-molecule PD1-PDL1 inhibitors is still in its infancy with no such drugs approved yet. Nevertheless, a promising series of small molecules inducing PDL1 dimerization has revealed important spatio-chemical features required for effective PD1-PDL1 inhibition through PDL1 sequestration. In the present study, we utilized these features for developing machine-learning (ML) classifiers by fitting Random Forest models to six 2D fingerprint descriptors. A focused database of ~16 K bioactive molecules, including approved and experimental drugs, was screened using these ML models, leading to classification of 361 molecules as potentially active. These ML hits were subjected to molecular docking studies to further shortlist them based on their binding interactions within the PDL1 dimer pocket. The top 20 molecules with favorable interactions were experimentally tested using HTRF human PD1-PDL1 binding assays, leading to the identification of two active molecules, CRT5 and P053, with the IC50 values of 22.35 and 33.65 µM, respectively. Owing to their bioactive nature, our newly discovered molecules may prove suitable for further medicinal chemistry optimization, leading to more potent and selective PD1-PDL1 inhibitors. Finally, our ML models and the integrated screening protocol may prove useful for screening larger libraries for novel PD1-PDL1 inhibitors. Full article
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Article
Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core
Pharmaceuticals 2022, 15(4), 444; https://doi.org/10.3390/ph15040444 - 02 Apr 2022
Viewed by 871
Abstract
The use of p53-MDM2 inhibitors is a prospective strategy in anti-cancer therapy for tumors expressing wild type p53 protein. In this study, we have applied a simple approach of two-step synthesis of imidazoline-based alkoxyaryl compounds, which are able to efficiently inhibit p53-MDM2 protein–protein [...] Read more.
The use of p53-MDM2 inhibitors is a prospective strategy in anti-cancer therapy for tumors expressing wild type p53 protein. In this study, we have applied a simple approach of two-step synthesis of imidazoline-based alkoxyaryl compounds, which are able to efficiently inhibit p53-MDM2 protein–protein interactions, promote accumulation of p53 and p53-inducible proteins in various cancer cell lines. Compounds 2l and 2k cause significant upregulation of p53 and p53-inducible proteins in five human cancer cell lines, one of which possesses overexpression of MDM2. Full article
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