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Dual Targeting as a Strategy to Counteract Chronic Diseases

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

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 12789

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Special Issue Editors

Prof. Dr. David M. Pereira

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Guest Editor

Laboratory of Pharmacognosy, Faculty of Pharmacy, University of Porto, Porto, Portugal
Interests: natural products chemistry; bioactive small molecules; anti-inflammatory drugs; pro-apoptotic drugs; endoplasmic reticulum stress; proteasome inhibitors
Special Issues, Collections and Topics in MDPI journals

Dr. Renato B. Pereira

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Guest Editor

Laboratory of Pharmacognosy, Faculty of Pharmacy, University of Porto, Portugal
Interests: marine natural products; inflammation; NF-κB inhibitors; iNOS modulators; NLRP3 inflammasome inhibitors; cancer; pro-apoptotic molecules
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The notion of "one molecule—one target—one disease" has been a prevalent paradigm in the pharmaceutical industry. The main idea of this approach is the identification of a single target whose inhibition leads to a successful treatment of a specific disease. However, this paradigm neglects the fact that many diseases are multifactorial, and efficient treatment in such cases will require the modulation of several targets. The modulation of two biological targets with a single drug can lead to synergistic therapeutic effects and avoid side effects associated with combination therapy. Moreover, this strategy presents several advantages when compared with combined therapies, including more predictable pharmacokinetics, lower probabilities of drug interactions, and higher patient compliance.

The rationale for the development of dual targeting agents is also to overcome incomplete efficacy and drug resistance frequently present when applying single targeting agents, and is considered as a potential therapeutic solution to complex disorders, which are more likely healed or alleviated though the simultaneous modulation of multiple targets. Given this situation and the growing body of evidence that these new approaches are effective, dual target intervention appears to have great potential for discovering, designing, and developing effective new drugs for today's diseases.

This Special Issue will focus on the process of drug discovery of dual target molecules as well as their involvement in the simultaneous modulation of targets associated with chronic diseases, including but not limited to neurodegenerative diseases, chronic inflammation, and cancer.

Prof. Dr. David M. Pereira
Dr. Renato B. Pereira
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

dual target molecules
chronic diseases
polypharmacology
medicinal chemistry
drug discovery
rational design
natural products
cancer
inflammation
neurodegenerative diseases

Published Papers (3 papers)

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Research

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17 pages, 3106 KiB

Open AccessArticle

Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

by Ewa Witkowska, Magda Godlewska, Jowita Osiejuk, Sandra Gątarz, Beata Wileńska, Katarzyna Kosińska, Joanna Starnowska-Sokół, Anna Piotrowska, Piotr F. J. Lipiński, Joanna Matalińska, Jolanta Dyniewicz, Paweł K. Halik, Ewa Gniazdowska, Barbara Przewlocka and Aleksandra Misicka

Int. J. Mol. Sci. 2022, 23(2), 674; https://doi.org/10.3390/ijms23020674 - 08 Jan 2022

Cited by 5 | Viewed by 2140

Abstract

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors. Full article

(This article belongs to the Special Issue Dual Targeting as a Strategy to Counteract Chronic Diseases)

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Review

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21 pages, 364 KiB

Open AccessReview

Emerging Molecular Targets for Anti-Epileptogenic and Epilepsy Modifying Drugs

by Katarzyna Łukasiuk and Władysław Lasoń

Int. J. Mol. Sci. 2023, 24(3), 2928; https://doi.org/10.3390/ijms24032928 - 02 Feb 2023

Cited by 8 | Viewed by 2376

Abstract

The pharmacological treatment of epilepsy is purely symptomatic. Despite many decades of intensive research, causal treatment of this common neurologic disorder is still unavailable. Nevertheless, it is expected that advances in modern neuroscience and molecular biology tools, as well as improved animal models may accelerate designing antiepileptogenic and epilepsy-modifying drugs. Epileptogenesis triggers a vast array of genomic, epigenomic and transcriptomic changes, which ultimately lead to morphological and functional transformation of specific neuronal circuits resulting in the occurrence of spontaneous convulsive or nonconvulsive seizures. Recent decades unraveled molecular processes and biochemical signaling pathways involved in the proepileptic transformation of brain circuits including oxidative stress, apoptosis, neuroinflammatory and neurotrophic factors. The “omics” data derived from both human and animal epileptic tissues, as well as electrophysiological, imaging and neurochemical analysis identified a plethora of possible molecular targets for drugs, which could interfere with various stages of epileptogenetic cascade, including inflammatory processes and neuroplastic changes. In this narrative review, we briefly present contemporary views on the neurobiological background of epileptogenesis and discuss the advantages and disadvantages of some more promising molecular targets for antiepileptogenic pharmacotherapy. Full article

(This article belongs to the Special Issue Dual Targeting as a Strategy to Counteract Chronic Diseases)

32 pages, 8219 KiB

Open AccessReview

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

by Piotr F. J. Lipiński and Joanna Matalińska

Int. J. Mol. Sci. 2022, 23(5), 2766; https://doi.org/10.3390/ijms23052766 - 02 Mar 2022

Cited by 7 | Viewed by 7231

Abstract

One of the strategies in the search for safe and effective analgesic drugs is the design of multitarget analgesics. Such compounds are intended to have high affinity and activity at more than one molecular target involved in pain modulation. In the present contribution we summarize the attempts in which fentanyl or its substructures were used as a μ-opioid receptor pharmacophoric fragment and a scaffold to which fragments related to non-opioid receptors were attached. The non-opioid ‘second’ targets included proteins as diverse as imidazoline I₂ binding sites, CB₁ cannabinoid receptor, NK₁ tachykinin receptor, D₂ dopamine receptor, cyclooxygenases, fatty acid amide hydrolase and monoacylglycerol lipase and σ₁ receptor. Reviewing the individual attempts, we outline the chemistry, the obtained pharmacological properties and structure-activity relationships. Finally, we discuss the possible directions for future work. Full article

(This article belongs to the Special Issue Dual Targeting as a Strategy to Counteract Chronic Diseases)

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