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

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

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 9986

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Dr. Sachin P. Patil

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Guest Editor

School of Engineering, Widener University, Chester, PA 19013, USA
Interests: Alzheimer's disease; cancer; metabolic engineering; interactome engineering
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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

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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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2200 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 (7 papers)

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Open AccessArticle

Dehydroeburicoic Acid, a Dual Inhibitor against Oxidative Stress in Alcoholic Liver Disease

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Pharmaceuticals 2023, 16(1), 14; https://doi.org/10.3390/ph16010014 - 22 Dec 2022

Viewed by 802

Abstract

Alcoholic liver disease (ALD) is a complicated disease which can lead to hepatocellular carcinoma; however, there is a lack of satisfactory therapeutics. Dehydroeburicoic acid (DEA) (1), a triterpenoid isolated from Antrodia cinnamomea, has been reported to act against ALD, but its mechanisms of action are still not clear. In this study, we report for the first time the use of DEA (1) as a dual inhibitor of the Keap1–Nrf2 protein–protein interaction (PPI) and GSK3β in an in vitro ALD cell model. DEA (1) engages Keap1 to disrupt the Keap1–Nrf2 PPI and inhibits GSK3β to restore Nrf2 activity in a Keap1-independent fashion. DEA (1) promotes Nrf2 nuclear translocation to activate downstream antioxidant genes. Importantly, DEA (1) restores the mitochondrial dysfunction induced by ethanol and generates antioxidant activity in the ALD cell model with minimal toxicity. We anticipate that DEA (1) could be a potential scaffold for the further development of clinical agents for treating ALD. Full article

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

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Open AccessArticle

Rational Strategy for Designing Peptidomimetic Small Molecules Based on Cyclic Peptides Targeting Protein–Protein Interaction between CTLA-4 and B7-1

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Pharmaceuticals 2022, 15(12), 1506; https://doi.org/10.3390/ph15121506 - 02 Dec 2022

Viewed by 1304

Abstract

Currently, various pharmaceutical modalities are being developed rapidly. Targeting protein–protein interactions (PPIs) is an important objective in such development. Cyclic peptides, because they have good specificity and activity, have been attracting much attention as an alternative to antibody drugs. However, cyclic peptides involve some difficulties, such as oral availability and cell permeability. Therefore, while small-molecule drugs still present many benefits, the screening of functional small-molecule compounds targeting PPIs requires a great deal of time and effort, including structural analysis of targets and hits. In this study, we investigated a rational two-step strategy to design small-molecule compounds targeting PPIs. First, we obtained inhibitory cyclic peptides that bind to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) by ribosomal display using PUREfrex^® (PUREfrex^®RD) to get structure–activity relation (SAR) information. Based on that information, we converted cyclic peptides to small molecules using PepMetics^® scaffolds that can mimic the α-helix or β-turn of the peptide. Finally, we succeeded in generating small-molecule compounds with good IC₅₀ (single-digit μM values) against CTLA-4. This strategy is expected to be a useful approach for small-molecule design targeting PPIs, even without having structural information such as that associated with X-ray crystal structures. Full article

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

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Open AccessArticle

Broad-Spectrum Small-Molecule Inhibitors of the SARS-CoV-2 Spike—ACE2 Protein–Protein Interaction from a Chemical Space of Privileged Protein Binders

Sung-Ting Chuang

and

Peter Buchwald

Pharmaceuticals 2022, 15(9), 1084; https://doi.org/10.3390/ph15091084 - 30 Aug 2022

Cited by 2 | Viewed by 903

Abstract

Therapeutically useful small-molecule inhibitors (SMIs) of protein–protein interactions (PPIs) initiating the cell attachment and entry of viruses could provide novel alternative antivirals that act via mechanisms similar to that of neutralizing antibodies but retain the advantages of small-molecule drugs such as oral bioavailability and low likelihood of immunogenicity. From screening our library, which is focused around the chemical space of organic dyes to provide good protein binders, we have identified several promising SMIs of the SARS-CoV-2 spike—ACE2 interaction, which is needed for the attachment and cell entry of this coronavirus behind the COVID-19 pandemic. They included organic dyes, such as Congo red, direct violet 1, and Evans blue, which seem to be promiscuous PPI inhibitors, as well as novel drug-like compounds (e.g., DRI-C23041). Here, we show that in addition to the original SARS-CoV-2 strain, these SMIs also inhibit this PPI for variants of concern including delta (B.1.617.2) and omicron (B.1.1.529) as well as HCoV-NL63 with low- or even sub-micromolar activity. They also concentration-dependently inhibited SARS-CoV-2-S expressing pseudovirus entry into hACE2-expressing cells with low micromolar activity (IC₅₀ < 10 μM) both for the original strain and the delta variant. DRI-C23041 showed good therapeutic (selectivity) index, i.e., separation between activity and cytotoxicity (TI > 100). Specificities and activities require further optimization; nevertheless, these results provide a promising starting point toward novel broad-spectrum small-molecule antivirals that act via blocking the interaction between the spike proteins of coronaviruses and their ACE2 receptor initiating cellular entry. Full article

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

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Open AccessArticle

Rational Design by Structural Biology of Industrializable, Long-Acting Antihyperglycemic GLP-1 Receptor Agonists

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Pharmaceuticals 2022, 15(6), 740; https://doi.org/10.3390/ph15060740 - 13 Jun 2022

Viewed by 1785

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 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

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

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Open AccessArticle

Machine-Learning Guided Discovery of Bioactive Inhibitors of PD1-PDL1 Interaction

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Pharmaceuticals 2022, 15(5), 613; https://doi.org/10.3390/ph15050613 - 16 May 2022

Cited by 1 | Viewed by 1516

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 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

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

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Open AccessArticle

Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core

Daniil R. Bazanov

Nikolay V. Pervushin

Egor V. Savin

Michael D. Tsymliakov

Anita I. Maksutova

Victoria Yu. Savitskaya

Sergey E. Sosonyuk

Yulia A. Gracheva

Michael Yu. Seliverstov

Natalia A. Lozinskaya

and

Gelina S. Kopeina

Pharmaceuticals 2022, 15(4), 444; https://doi.org/10.3390/ph15040444 - 02 Apr 2022

Cited by 5 | Viewed by 1745

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 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

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

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Open AccessOpinion

Targeting Protein-Protein Interactions to Inhibit Cyclin-Dependent Kinases

Mark Klein

Pharmaceuticals 2023, 16(4), 519; https://doi.org/10.3390/ph16040519 - 31 Mar 2023

Viewed by 518

Abstract

Cyclin-dependent kinases (CDKs) play diverse and critical roles in normal cells and may be exploited as targets in cancer therapeutic strategies. CDK4 inhibitors are currently approved for treatment in advanced breast cancer. This success has led to continued pursuit of targeting other CDKs. One challenge has been in the development of inhibitors that are highly selective for individual CDKs as the ATP-binding site is highly conserved across this family of proteins. Protein-protein interactions (PPI) tend to have less conservation amongst different proteins, even within protein families, making targeting PPI an attractive approach to improving drug selectivity. However, PPI can be challenging to target due to structural and physicochemical features of these interactions. A review of the literature specific to studies focused on targeting PPI involving CDKs 2, 4, 5, and 9 was conducted and is presented here. Promising lead molecules to target select CDKs have been discovered. None of the lead molecules discovered have led to FDA approval; however, the studies covered in this review lay the foundation for further discovery and develop of PPI inhibitors for CDKs. Full article

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

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