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Multi-Target Directed Ligands in Drug Development

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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 (15 December 2023) | Viewed by 11204

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Special Issue Editors

Prof. Dr. Jan Korabecny

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Guest Editor

Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Interests: Alzheimer's disease; acetylcholinesterase; butyrylcholinesterase; organic synthesis; anticancer drugs; kinase inhibitors; molecular modeling studies; medicinal chemistry; organophosphorus intoxication; chemical warfare agents; acetylcholinesterase reactivators; in silico studies
Special Issues, Collections and Topics in MDPI journals

Dr. Dawid Panek

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Guest Editor

Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
Interests: acetylcholinesterase; butyrylcholinesterase; drug discovery; γ-butyric acid; γ aminobutyric acid transporters; glycogen synthase kinase 3β; nuclear factor kappa B; Alzheimer's disease; epilepsy; neuropathic pain; depression; beta-secretase; medicinal chemistry; organic chemistry

Special Issue Information

Dear Colleagues,

During the twentieth century, drug discovery efforts were concentrated on the dogma of “one-target-one disease”, which generated many drugs that are still in use. However, this concept was often ineffective for many diseases treated by single-targeted therapeutics. Given the high failure rate in the clinic or the lack of efficacy of several drug candidates, the beginning of the 21st century has witnessed the start and rise of the so-called "multi-target directed ligand" approach that is trying to address the complexity of the disease to provide the highest possible therapeutic feedback. Thus, multi-target drugs aiming simultaneously at several subpathologies are expected to be a better approach compared to single-oriented bullets. In this Special Issue, we would like to encourage researchers from different fields of research to submit their original, as well as review, articles with a primary focus on multi-target-directed ligands from different perspectives and conditions. Indeed, the strategy exploiting multi-target-directed ligands has successfully been engaged in the therapy of many diseases such as hypertension, hyperlipidemia, cancer, HIV, cardiovascular disease, depression, pain, inflammation, infectious and neurodegenerative diseases, among others.

Prof. Dr. Jan Korabecny
Dr. Dawid Panek
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

multi-target-directed ligands
drug discovery
drug design
multi-target ligands
chemical synthesis
biological activity
drug targets
neurodegenerative diseases
cancer
hypertension
hyperlipidemia
HIV
cardiovascular disease
depression
inflammation
infectious diseases
polypharmacology

Published Papers (4 papers)

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Research

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28 pages, 9223 KiB

Open AccessArticle

Structure-Guided Design of N-Methylpropargylamino-Quinazoline Derivatives as Multipotent Agents for the Treatment of Alzheimer’s Disease

by Barbora Svobodova, Lenka Pulkrabkova, Dawid Panek, Anna Misiachna, Marharyta Kolcheva, Rudolf Andrys, Jiri Handl, Jan Capek, Pavlina Nyvltova, Tomas Rousar, Lukas Prchal, Vendula Hepnarova, Martina Hrabinova, Lubica Muckova, Daniela Tosnerova, Galina Karabanovich, Vladimir Finger, Ondrej Soukup, Martin Horak and Jan Korabecny

Int. J. Mol. Sci. 2023, 24(11), 9124; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24119124 - 23 May 2023

Viewed by 2346

Abstract

Alzheimer’s disease (AD) is a complex disease with an unknown etiology. Available treatments, limited to cholinesterase inhibitors and N-methyl-d-aspartate receptor (NMDAR) antagonists, provide symptomatic relief only. As single-target therapies have not proven effective, rational specific-targeted combination into a single molecule represents a more promising approach for treating AD, and is expected to yield greater benefits in alleviating symptoms and slowing disease progression. In the present study, we designed, synthesized, and biologically evaluated 24 novel N-methylpropargylamino-quinazoline derivatives. Initially, compounds were thoroughly inspected by in silico techniques determining their oral and CNS availabilities. We tested, in vitro, the compounds’ effects on cholinesterases and monoamine oxidase A/B (MAO-A/B), as well as their impacts on NMDAR antagonism, dehydrogenase activity, and glutathione levels. In addition, we inspected selected compounds for their cytotoxicity on undifferentiated and differentiated neuroblastoma SH-SY5Y cells. We collectively highlighted II-6h as the best candidate endowed with a selective MAO-B inhibition profile, NMDAR antagonism, an acceptable cytotoxicity profile, and the potential to permeate through BBB. The structure-guided drug design strategy applied in this study imposed a novel concept for rational drug discovery and enhances our understanding on the development of novel therapeutic agents for treating AD. Full article

(This article belongs to the Special Issue Multi-Target Directed Ligands in Drug Development)

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25 pages, 8584 KiB

Open AccessArticle

A Search for Cyclin-Dependent Kinase 4/6 Inhibitors by Pharmacophore-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations

by Ni Made Pitri Susanti, Sophi Damayanti, Rahmana Emran Kartasasmita and Daryono Hadi Tjahjono

Int. J. Mol. Sci. 2021, 22(24), 13423; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413423 - 14 Dec 2021

Cited by 5 | Viewed by 2275

Abstract

The G1 phase of cell cycle progression is regulated by Cyclin-Dependent Kinase 4 (CDK4) as well as Cyclin-Dependent Kinase 6 (CDK6), and the acivities of these enzymes are regulated by the catalytic subunit, cyclin D. Cell cycle control through selective pharmacological inhibition of CDK4/6 has proven to be beneficial in the treatment of estrogen receptor-positive (ER-positive) breast cancer, particularly improving the progression-free survival of patients. Thus, targeting specific inhibition on CDK4/6 is bound to increase therapeutic efficiency. This study aimed to obtain CDK4/6 inhibitors through a pharmacophore-based virtual screening of the ZINC15 purchasable compound database using the in silico method. The pharmacophore model was designed based on the FDA-approved cdk4/6 inhibitor structures, and molecular docking was performed to further screen the hit compounds obtained. A total of eight compounds were selected based on docking results and interactions with CDK4 and CDK6, using palbociclib as the reference drug. According to the results, the compounds of ZINC585292724 and ZINC585291674 were the best compounds based on free binding energy, as well as hydrogen bond stability, and, therefore, exhibit potential as starting points in the development of CDK4/6 inhibitors. Full article

(This article belongs to the Special Issue Multi-Target Directed Ligands in Drug Development)

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Review

Jump to: Research

23 pages, 2617 KiB

Open AccessReview

Natural Alkaloids as Multi-Target Compounds towards Factors Implicated in Alzheimer’s Disease

by Rudolf Vrabec, Gerald Blunden and Lucie Cahlíková

Int. J. Mol. Sci. 2023, 24(5), 4399; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054399 - 23 Feb 2023

Cited by 12 | Viewed by 2977

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in elderly people; currently, there is no efficient treatment. Considering the increase in life expectancy worldwide AD rates are predicted to increase enormously, and thus the search for new AD drugs is urgently needed. A great amount of experimental and clinical evidence indicated that AD is a complex disorder characterized by widespread neurodegeneration of the CNS, with major involvement of the cholinergic system, causing progressive cognitive decline and dementia. The current treatment, based on the cholinergic hypothesis, is only symptomatic and mainly involves the restoration of acetylcholine (ACh) levels through the inhibition of acetylcholinesterase (AChE). Since the introduction of the Amaryllidaceae alkaloid galanthamine as an antidementia drug in 2001, alkaloids have been one of the most attractive groups for searching for new AD drugs. The present review aims to comprehensively summarize alkaloids of various origins as multi-target compounds for AD. From this point of view, the most promising compounds seem to be the β-carboline alkaloid harmine and several isoquinoline alkaloids since they can simultaneously inhibit several key enzymes of AD’s pathophysiology. However, this topic remains open for further research on detailed mechanisms of action and the synthesis of potentially better semi-synthetic analogues. Full article

(This article belongs to the Special Issue Multi-Target Directed Ligands in Drug Development)

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20 pages, 1442 KiB

Open AccessReview

Tricyclodecan-9-yl-Xanthogenate (D609): Mechanism of Action and Pharmacological Applications

by Aashiq Hussain Bhat, Khalid Bashir Dar, Andleeb Khan, Saeed Alshahrani, Sultan M. Alshehri, Mohammed M. Ghoneim, Prawez Alam and Faiyaz Shakeel

Int. J. Mol. Sci. 2022, 23(6), 3305; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063305 - 18 Mar 2022

Cited by 1 | Viewed by 2360

Abstract

Tricyclodecan-9-yl xanthogenate (D609) is a synthetic tricyclic compound possessing a xanthate group. This xanthogenate compound is known for its diverse pharmacological properties. Over the last three decades, many studies have reported the biological activities of D609, including antioxidant, antiapoptotic, anticholinergic, anti-tumor, anti-inflammatory, anti-viral, anti-proliferative, and neuroprotective activities. Its mechanism of action is extensively attributed to its ability to cause the competitive inhibition of phosphatidylcholine (PC)-specific phospholipase C (PC-PLC) and sphingomyelin synthase (SMS). The inhibition of PCPLC or SMS affects secondary messengers with a lipidic nature, i.e., 1,2-diacylglycerol (DAG) and ceramide. Various in vitro/in vivo studies suggest that PCPLC and SMS inhibition regulate the cell cycle, block cellular proliferation, and induce differentiation. D609 acts as a pro-inflammatory cytokine antagonist and diminishes Aβ-stimulated toxicity. PCPLC enzymatic activity essentially requires Zn²⁺, and D609 might act as a potential chelator of Zn²⁺, thereby blocking PCPLC enzymatic activity. D609 also demonstrates promising results in reducing atherosclerotic plaque formation, post-stroke cerebral infarction, and cancer progression. The present compilation provides a comprehensive mechanistic insight into D609, including its chemistry, mechanism of action, and regulation of various pharmacological activities. Full article

(This article belongs to the Special Issue Multi-Target Directed Ligands in Drug Development)

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