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Exploiting the Multitarget and Repositioned Drugs Approach

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 20178

Special Issue Editor

Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, Via E. Orabona 4, 70125 Bari, Italy
Interests: drug design; QSAR; molecular docking; virtual screening; homology modelling; molecular dynamics; GPCRs; metabolic diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Hyperspecialization assists the welfare state in different disciplines, such as economics, engineering, medicine, the life sciences and even sports, positively affecting our lifestyle. This higher level of knowledge has also been widely applied to the drug design process and discovery, where the urgent need to search for molecular entities acting as a selective magic bullet piloted the rise of blockbuster drugs in the golden age of pharmaceutics. In the 1990s, the largest pharmaceutical companies struggled, searching for extremely narrow needles in very big haystacks, with projects and pipeline tools to maximize their efforts and expenses through studies focusing on highly selective research lines. Their studies were often based on models which were able to extract the maximum in terms of biological activity and selectivity from a limited and definite number of chemical clichés.

This scenario is, indeed, in development, widening to a multitarget approach aiming to discover ‘one size fit all’, compounds allowing the stakeholders to reduce costs and increase benefits, and simultaneously increasing the efficacy and yields of the marketed products. Nonetheless, the reuse and recycle philosophy is also applied to the retargeting of pre-existing drugs. 

This Special Issue will present a collection of papers and case studies, focusing on highly relevant subjects like multifactorial, neurodegenerative, cardiovascular and metabolic diseases, and cancer, based on experimental (synthesis, enzymatic assays) and theoretical (computational and modelling studies) techniques, unravelling unexpected polypharmacological effects for novel synthetic as well as natural compounds. It will present original research and protocols to shed light on this very challenging, but attractive, field, and short communications and reviews will also be welcomed.

Prof. Dr. Antonio Carrieri
Guest Editor

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Keywords

  • multifactorial diseases
  • metabolic syndrome
  • cancer
  • drug repositioning
  • virtual screening
  • target fishing
  • docking

Published Papers (7 papers)

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Research

13 pages, 2174 KiB  
Article
Resemblance-Ranking Peptide Library to Screen for Binders to Antibodies on a Peptidomic Scale
by Felix Jenne, Sergey Biniaminov, Nathalie Biniaminov, Philipp Marquardt, Clemens von Bojničić-Kninski, Roman Popov, Anja Seckinger, Dirk Hose and Alexander Nesterov-Mueller
Int. J. Mol. Sci. 2022, 23(7), 3515; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073515 - 23 Mar 2022
Cited by 2 | Viewed by 2130
Abstract
A novel resemblance-ranking peptide library with 160,000 10-meric peptides was designed to search for selective binders to antibodies. The resemblance-ranking principle enabled the selection of sequences that are most similar to the human peptidome. The library was synthesized with ultra-high-density peptide arrays. As [...] Read more.
A novel resemblance-ranking peptide library with 160,000 10-meric peptides was designed to search for selective binders to antibodies. The resemblance-ranking principle enabled the selection of sequences that are most similar to the human peptidome. The library was synthesized with ultra-high-density peptide arrays. As proof of principle, screens for selective binders were performed for the therapeutic anti-CD20 antibody rituximab. Several features in the amino acid composition of antibody-binding peptides were identified. The selective affinity of rituximab increased with an increase in the number of hydrophobic amino acids in a peptide, mainly tryptophan and phenylalanine, while a total charge of the peptide remained relatively small. Peptides with a higher affinity exhibited a lower sum helix propensity. For the 30 strongest peptide binders, a substitutional analysis was performed to determine dissociation constants and the invariant amino acids for binding to rituximab. The strongest selective peptides had a dissociation constant in the hundreds of the nano-molar range. The substitutional analysis revealed a specific hydrophobic epitope for rituximab. To show that conformational binders can, in principle, be detected in array format, cyclic peptide substitutions that are similar to the target of rituximab were investigated. Since the specific binders selected via the resemblance-ranking peptide library were based on the hydrophobic interactions that are widespread in the world of biomolecules, the library can be used to screen for potential linear epitopes that may provide information about the cross-reactivity of antibodies. Full article
(This article belongs to the Special Issue Exploiting the Multitarget and Repositioned Drugs Approach)
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27 pages, 5464 KiB  
Article
Identification of Nifurtimox and Chrysin as Anti-Influenza Virus Agents by Clinical Transcriptome Signature Reversion
by Yijing Xin, Shubing Chen, Ke Tang, You Wu and Ying Guo
Int. J. Mol. Sci. 2022, 23(4), 2372; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042372 - 21 Feb 2022
Cited by 3 | Viewed by 2394
Abstract
The rapid development in the field of transcriptomics provides remarkable biomedical insights for drug discovery. In this study, a transcriptome signature reversal approach was conducted to identify the agents against influenza A virus (IAV) infection through dissecting gene expression changes in response to [...] Read more.
The rapid development in the field of transcriptomics provides remarkable biomedical insights for drug discovery. In this study, a transcriptome signature reversal approach was conducted to identify the agents against influenza A virus (IAV) infection through dissecting gene expression changes in response to disease or compounds’ perturbations. Two compounds, nifurtimox and chrysin, were identified by a modified Kolmogorov–Smirnov test statistic based on the transcriptional signatures from 81 IAV-infected patients and the gene expression profiles of 1309 compounds. Their activities were verified in vitro with half maximal effective concentrations (EC50s) from 9.1 to 19.1 μM against H1N1 or H3N2. It also suggested that the two compounds interfered with multiple sessions in IAV infection by reversing the expression of 28 IAV informative genes. Through network-based analysis of the 28 reversed IAV informative genes, a strong synergistic effect of the two compounds was revealed, which was confirmed in vitro. By using the transcriptome signature reversion (TSR) on clinical datasets, this study provides an efficient scheme for the discovery of drugs targeting multiple host factors regarding clinical signs and symptoms, which may also confer an opportunity for decelerating drug-resistant variant emergence. Full article
(This article belongs to the Special Issue Exploiting the Multitarget and Repositioned Drugs Approach)
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26 pages, 3242 KiB  
Article
Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness
by Francisco J. Carrera Arias, Kristina Aenlle, Maria Abreu, Mary A. Holschbach, Lindsay T. Michalovicz, Kimberly A. Kelly, Nancy Klimas, James P. O’Callaghan and Travis J. A. Craddock
Int. J. Mol. Sci. 2021, 22(16), 8546; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168546 - 09 Aug 2021
Cited by 7 | Viewed by 2752
Abstract
Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain [...] Read more.
Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic–pituitary–adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood–brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic–pituitary–gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA–HPG–Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal–glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI. Full article
(This article belongs to the Special Issue Exploiting the Multitarget and Repositioned Drugs Approach)
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14 pages, 15291 KiB  
Article
Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro
by Hirofumi Ohashi, Feng Wang, Frank Stappenbeck, Kana Tsuchimoto, Chisa Kobayashi, Wakana Saso, Michiyo Kataoka, Masako Yamasaki, Kouji Kuramochi, Masamichi Muramatsu, Tadaki Suzuki, Camille Sureau, Makoto Takeda, Takaji Wakita, Farhad Parhami and Koichi Watashi
Int. J. Mol. Sci. 2021, 22(6), 3163; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063163 - 19 Mar 2021
Cited by 20 | Viewed by 4198
Abstract
The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates [...] Read more.
The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates for the inhibition of cancer, fibrosis, and bone regeneration. In this study, we screened a panel of naturally occurring and semi-synthetic oxysterols for anti-SARS-CoV-2 activity using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 μM and 99% at 15 μM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 μM), based on the dose-dependent curve for antiviral activity in our cell-based assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 by disrupting the formation of double-membrane vesicles (DMVs); intracellular membrane compartments associated with viral replication. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk of developing COVID-19. Full article
(This article belongs to the Special Issue Exploiting the Multitarget and Repositioned Drugs Approach)
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8 pages, 978 KiB  
Article
Discovery of a Bradykinin B2 Partial Agonist Profile of Raloxifene in a Drug Repurposing Campaign
by Patricia Gomez-Gutierrez and Juan J. Perez
Int. J. Mol. Sci. 2021, 22(1), 257; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010257 - 29 Dec 2020
Cited by 3 | Viewed by 2744
Abstract
Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in illness progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing. Recently, it was suggested that a dysregulated bradykinin signaling can trigger the cytokine [...] Read more.
Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in illness progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing. Recently, it was suggested that a dysregulated bradykinin signaling can trigger the cytokine storm observed in patients with severe Covid-19. In the scope of a drug repurposing campaign undertaken to identify bradykinin antagonists, raloxifene was identified as prospective compound in a virtual screening process. The pharmacodynamics profile of raloxifene towards bradykinin receptors is reported in the present work, showing a weak selective partial agonist profile at the B2 receptor. In view of this new profile, its possible use as a therapeutical agent for the treatment of severe Covid-19 is discussed. Full article
(This article belongs to the Special Issue Exploiting the Multitarget and Repositioned Drugs Approach)
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25 pages, 23931 KiB  
Article
Molecular Modeling Study of c-KIT/PDGFRα Dual Inhibitors for the Treatment of Gastrointestinal Stromal Tumors
by Seketoulie Keretsu, Suparna Ghosh and Seung Joo Cho
Int. J. Mol. Sci. 2020, 21(21), 8232; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218232 - 03 Nov 2020
Cited by 16 | Viewed by 2811
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common Mesenchymal Neoplasm of the gastrointestinal tract. The tumorigenesis of GISTs has been associated with the gain-of-function mutation and abnormal activation of the stem cell factor receptor (c-KIT) and platelet-derived growth factor receptor alpha (PDGFRα) kinases. [...] Read more.
Gastrointestinal stromal tumors (GISTs) are the most common Mesenchymal Neoplasm of the gastrointestinal tract. The tumorigenesis of GISTs has been associated with the gain-of-function mutation and abnormal activation of the stem cell factor receptor (c-KIT) and platelet-derived growth factor receptor alpha (PDGFRα) kinases. Hence, inhibitors that target c-KIT and PDGFRα could be a therapeutic option for the treatment of GISTs. The available approved c-KIT/PDGFRα inhibitors possessed low efficacy with off-target effects, which necessitated the development of potent inhibitors. We performed computational studies of 48 pyrazolopyridine derivatives that showed inhibitory activity against c-KIT and PDGFRα to study the structural properties important for inhibition of both the kinases. The derivative of phenylurea, which has high activities for both c-KIT (pIC50 = 8.6) and PDGFRα (pIC50 = 8.1), was used as the representative compound for the dataset. Molecular docking and molecular dynamics simulation (100 ns) of compound 14 was performed. Compound 14 showed the formation of hydrogen bonding with Cys673, Glu640, and Asp810 in c-KIT, and Cys677, Glu644, and Asp836 in PDGFRα. The results also suggested that Thr670/T674 substitution in c-KIT/PDGFRα induced conformational changes at the binding site of the receptors. Three-dimensional quantitative structure–activity relationship (3D-QSAR) models were developed based on the inhibitors. Contour map analysis showed that electropositive and bulky substituents at the para-position and the meta-position of the benzyl ring of compound 14 was favorable and may increase the inhibitory activity against both c-KIT and PDGFRα. Analysis of the results suggested that having bulky and hydrophobic substituents that extend into the hydrophobic pocket of the binding site increases the activity for both c-KIT and PDGFRα. Based on the contour map analysis, 50 compounds were designed, and the activities were predicted. An evaluation of binding free energy showed that eight of the designed compounds have potential binding affinity with c-KIT/PDGFRα. Absorption, distribution, metabolism, excretion and toxicity (ADMET) and synthetic feasibility tests showed that the designed compounds have reasonable pharmaceutical properties and synthetic feasibility. Further experimental study of the designed compounds is recommended. The structural information from this study could provide useful insight into the future development of c-KIT and PDGFRα inhibitors. Full article
(This article belongs to the Special Issue Exploiting the Multitarget and Repositioned Drugs Approach)
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20 pages, 2712 KiB  
Article
Beyond the Canonical Endocannabinoid System. A Screening of PPAR Ligands as FAAH Inhibitors
by Leonardo Brunetti, Antonio Carrieri, Luca Piemontese, Paolo Tortorella, Fulvio Loiodice and Antonio Laghezza
Int. J. Mol. Sci. 2020, 21(19), 7026; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197026 - 24 Sep 2020
Cited by 8 | Viewed by 2357
Abstract
In recent years, Peroxisome Proliferator-Activated Receptors (PPARs) have been connected to the endocannabinoid system. These nuclear receptors indeed mediate the effects of anandamide and similar substances such as oleoyl-ethanolamide and palmitoyl-ethanolamide. An increasing body of literature describing the interactions between the endocannabinoid system [...] Read more.
In recent years, Peroxisome Proliferator-Activated Receptors (PPARs) have been connected to the endocannabinoid system. These nuclear receptors indeed mediate the effects of anandamide and similar substances such as oleoyl-ethanolamide and palmitoyl-ethanolamide. An increasing body of literature describing the interactions between the endocannabinoid system and PPARs has slowly but surely been accumulating over the past decade, and a multitarget approach involving these receptors and endocannabinoid degrading enzyme FAAH has been proposed for the treatment of inflammatory states, cancer, and Alzheimer’s disease. The lack of knowledge about compounds endowed with such an activity profile therefore led us to investigate a library of readily available, well-characterized PPAR agonists that we had synthesized over the years in order to find a plausible lead compound for further development. Moreover, we propose a rationalization of our results via a docking study, which sheds some light on the binding mode of these PPAR agonists to FAAH and opens the way for further research in this field. Full article
(This article belongs to the Special Issue Exploiting the Multitarget and Repositioned Drugs Approach)
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