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Polypharmacology and Multitarget Drug Discovery

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (20 May 2017) | Viewed by 113966

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Prof. Dr. Cornelis J. Van der Schyf

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Vice President for Research and Dean of the Graduate School, Professor of Biomedical and Pharmaceutical Sciences, Idaho State University, 921 S. 8th Avenue, Pocatello, ID 83209-0001, USA
Interests: neurodegenerative diseases; drug discovery; aging; multiple mechanism drugs
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Special Issue Information

Dear Colleagues,

Over the past two decades, a resurging interest in the development of multi-target directed compounds to treat diseases with complex pathological mechanisms has grown into one of the most actively investigated fields in the search for new drug molecules. Such drug molecules—previously referred to as “dirty drugs”, due to their clinically challenging and complex side-effect profiles in general use—simultaneously target multiple etiologies that have been found to be important modulators in a variety of diseases. This approach has been found to have significant promise for translation into the clinic and may be more effective than using one compound specifically targeted towards one molecular pathology or even a polypharmaceutical approach using a cocktail of two or more “pure” target-directed drugs.

However, the rational design and development of multi-target directed molecules remain one of the most challenging tasks facing medicinal chemists today. These challenges center around these key questions: (1) how does one achieve optimized activity towards multiple molecular targets of interest in the disease pathological pathways; (2) while simultaneously preserving drug-like properties and a balanced pharmacodynamics profile in one molecule; and (3) without compromising favorable pharmacokinetics?

Several chemical classes of structures have been found to be useful as scaffolds to be considered for multitarget drugs in drug development programs.

This Special Issue attempts to provide a synopsis of current research by leaders in the field, and will exemplify the use of an array of approaches and particular compounds of interest used as starting molecules to develop multifunctional drugs, and will emphasize innovative applications of multifunctional and hybrid molecules in challenging and complex diseases.

We welcome original articles and short communications as well as a limited number of review articles on novel methods and approaches for multi-target directed drug development. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Prof. Dr. Cornelis J. Van Der Schyf
Guest Editor

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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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

multitarget-directed molecules
constructive polypharmacology
hybrid molecules
drug discovery
rational design
biomarkers
imaging agents
complex diseases

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Published Papers (11 papers)

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Research

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2424 KiB

Open AccessCommunication

MTLD, a Database of Multiple Target Ligands, the Updated Version

by Chao Chen, Meng Wu, Shan Cen, Jianhui Wu and Jinming Zhou

Molecules 2017, 22(9), 1375; https://doi.org/10.3390/molecules22091375 - 6 Sep 2017

Cited by 7 | Viewed by 5585

Abstract

Polypharmacology plays an important role in drug discovery and polypharmacology drug strategies provide a novel path in drug design. However, to develop a polypharmacology drug with the desired profile remains a challenge. Previously, we developed a free web-accessible database called Multiple Target Ligand Database (MTLD, www.mtdcadd.com). Herein, the MTLD database has been updated, containing 2444 Multiple Target Ligands (MTLs) that bind with 21,424 binding sites from 18,231 crystal structures. Of the MTLs, 304 entries are approved drugs, and 1911 entries are drug-like compounds. Also, we added new functions such as multiple conditional search and linkage visualization. Through querying the updated database, extremely useful information for the development of polypharmacology drugs may be provided. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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Open AccessArticle

Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation

by Patrick M. Kelly, Niall O. Keely, Sandra A. Bright, Bassem Yassin, Gloria Ana, Darren Fayne, Daniela M. Zisterer and Mary J. Meegan

Molecules 2017, 22(9), 1440; https://doi.org/10.3390/molecules22091440 - 31 Aug 2017

Cited by 29 | Viewed by 6770

Abstract

Nuclear receptors such as the estrogen receptors (ERα and ERβ) modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A-4 were synthesised and evaluated as ER ligands. A number of these compounds demonstrated pro-apoptotic effects, with potent antiproliferative activity in ER-positive MCF-7 breast cancer cell lines and low cytotoxicity. These conjugates displayed binding affinity towards ERα and ERβ isoforms at nanomolar concentrations e.g., the cyclofenil-amide compound 13e is a promising lead compound of a clinically relevant ER conjugate with IC₅₀ in MCF-7 cells of 187 nM, and binding affinity to ERα (IC₅₀ = 19 nM) and ERβ (IC₅₀ = 229 nM) while the endoxifen conjugate 16b demonstrates antiproliferative activity in MCF-7 cells (IC₅₀ = 5.7 nM) and binding affinity to ERα (IC₅₀ = 15 nM) and ERβ (IC₅₀ = 115 nM). The ER binding effects are rationalised in a molecular modelling study in which the disruption of the ER helix-12 in the presence of compounds 11e, 13e and 16b is presented These conjugate compounds have potential application for further development as antineoplastic agents in the treatment of ER positive breast cancers. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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2049 KiB

Open AccessArticle

Multifunctional Cinnamic Acid Derivatives

by Aikaterini Peperidou, Eleni Pontiki, Dimitra Hadjipavlou-Litina, Efstathia Voulgari and Konstantinos Avgoustakis

Molecules 2017, 22(8), 1247; https://doi.org/10.3390/molecules22081247 - 25 Jul 2017

Cited by 51 | Viewed by 9618

Abstract

Our research to discover potential new multitarget agents led to the synthesis of 10 novel derivatives of cinnamic acids and propranolol, atenolol, 1-adamantanol, naphth-1-ol, and (benzylamino) ethan-1-ol. The synthesized molecules were evaluated as trypsin, lipoxygenase and lipid peroxidation inhibitors and for their cytotoxicity. Compound 2b derived from phenoxyphenyl cinnamic acid and propranolol showed the highest lipoxygenase (LOX) inhibition (IC₅₀ = 6 μΜ) and antiproteolytic activity (IC₅₀ = 0.425 μΜ). The conjugate 1a of simple cinnamic acid with propranolol showed the higher antiproteolytic activity (IC₅₀ = 0.315 μΜ) and good LOX inhibitory activity (IC₅₀ = 66 μΜ). Compounds 3a and 3b, derived from methoxylated caffeic acid present a promising combination of in vitro inhibitory and antioxidative activities. The S isomer of 2b also presented an interesting multitarget biological profile in vitro. Molecular docking studies point to the fact that the theoretical results for LOX-inhibitor binding are identical to those from preliminary in vitro study. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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3822 KiB

Open AccessArticle

Molecular Docking and Anticonvulsant Activity of Newly Synthesized Quinazoline Derivatives

by Hatem A. Abuelizz, Rabab El Dib, Mohamed Marzouk, El-Hassane Anouar, Yousreya A. Maklad, Hanan N. Attia and Rashad Al-Salahi

Molecules 2017, 22(7), 1094; https://doi.org/10.3390/molecules22071094 - 30 Jun 2017

Cited by 63 | Viewed by 11405

Abstract

A new series of quinazoline-4(3H)-ones are evaluated for anticonvulsant activity. After intraperitoneal (ip) injection to albino mice at a dose of 100 mg/kg body weight, synthesized quinazolin-4(3H)-ones (1–24) were examined in the maximal electroshock (MES) induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The Rotarod method was applied to determine the neurotoxicity. Most of the compounds displayed anticonvulsant activity in the scPTZ screen at a dose range of 0.204–0.376 mmol/mL. Out of twenty-four, compounds 8, 13 and 19 proved to be the most active with a remarkable protection (100%) against PTZ induced convulsions and four times more potent activity than ethosuximide. The structure-activity relationship concluded valuable pharmacophoric information, which was confirmed by the molecular docking studies using the target enzyme human carbon anhydrase II (HCA II). The studied quinazoline analogues suggested that the butyl substitution at position 3 has a significant effect on preventing the spread of seizure discharge and on raising the seizure threshold. However, benzyl substitution at position 3 has shown a strong anticonvulsant activity but with less seizure prevention compared to the butyl substitution. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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1828 KiB

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Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson’s Disease

by Xuebao Wang, Chao Han, Yong Xu, Kaiqi Wu, Shuangya Chen, Mangsha Hu, Luyao Wang, Yun Ye and Faqing Ye

Molecules 2017, 22(6), 1010; https://doi.org/10.3390/molecules22061010 - 17 Jun 2017

Cited by 16 | Viewed by 6156

Abstract

The aim of this research was to prove the speculation that phenylxanthine (PX) derivatives possess adenosine A2A receptor (A2AR)-blocking properties and to screening and evaluate these PX derivatives as dual A2AR antagonists/MAO-B inhibitors for Parkinson′s disease. To explore this hypothesis, two series of PX derivatives were prepared and their antagonism against A2AR and inhibition against MAO-B were determined in vitro. In order to evaluate further the antiparkinsonian properties, pharmacokinetic and haloperidol-induced catalepsy experiments were carried out in vivo. The PX-D and PX-E analogues acted as potent A2AR antagonists with Ki values ranging from 0.27 to 10 μM, and these analogues displayed relatively mild MAO-B inhibition potencies, with inhibitor dissociation constants (Ki values) ranging from 0.25 to 10 μM. Further, the compounds PX-D-P6 and PX-E-P8 displayed efficacious antiparkinsonian properties in haloperidol-induced catalepsy experiments, verifying that these two compounds were potent A2AR antagonists and MAO-B inhibitors. We conclude that PX-D and PX-E analogues are a promising candidate class of dual-acting compounds for treating Parkinson′s disease. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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1976 KiB

Open AccessArticle

Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

by Katarina Spilovska, Jan Korabecny, Vendula Sepsova, Daniel Jun, Martina Hrabinova, Petr Jost, Lubica Muckova, Ondrej Soukup, Jana Janockova, Tomas Kucera, Rafael Dolezal, Eva Mezeiova, Daniel Kaping and Kamil Kuca

Molecules 2017, 22(6), 1006; https://doi.org/10.3390/molecules22061006 - 16 Jun 2017

Cited by 43 | Viewed by 7997

Abstract

A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer’s agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC₅₀ = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC₅₀ ≥ 500 μM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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11158 KiB

Open AccessArticle

Multi-Anti-Parasitic Activity of Arylidene Ketones and Thiazolidene Hydrazines against Trypanosoma cruzi and Leishmania spp.

by Guzmán Álvarez, Cintya Perdomo, Cathia Coronel, Elena Aguilera, Javier Varela, Gonzalo Aparicio, Flavio R. Zolessi, Nallely Cabrera, Celeste Vega, Miriam Rolón, Antonieta Rojas de Arias, Ruy Pérez-Montfort, Hugo Cerecetto and Mercedes González

Molecules 2017, 22(5), 709; https://doi.org/10.3390/molecules22050709 - 7 May 2017

Cited by 25 | Viewed by 5931

Abstract

A series of fifty arylideneketones and thiazolidenehydrazines was evaluated against Leishmania infantum and Leishmania braziliensis. Furthermore, new simplified thiazolidenehydrazine derivatives were evaluated against Trypanosoma cruzi. The cytotoxicity of the active compounds on non-infected fibroblasts or macrophages was established in vitro to evaluate the selectivity of their anti-parasitic effects. Seven thiazolidenehydrazine derivatives and ten arylideneketones had good activity against the three parasites. The IC₅₀ values for T. cruzi and Leishmania spp. ranged from 90 nM–25 µM. Eight compounds had multi-trypanocidal activity against T. cruzi and Leishmania spp. (the etiological agents of cutaneous and visceral forms). The selectivity of these active compounds was better than the three reference drugs: benznidazole, glucantime and miltefosine. They also had low toxicity when tested in vivo on zebrafish. Trying to understand the mechanism of action of these compounds, two possible molecular targets were investigated: triosephosphate isomerase and cruzipain. We also used a molecular stripping approach to elucidate the minimal structural requirements for their anti-T. cruzi activity. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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1072 KiB

Open AccessCommunication

Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase

by Karin Meirer, Daniel Glatzel, Simon Kretschmer, Sandra K. Wittmann, Markus Hartmann, René Blöcher, Carlo Angioni, Gerd Geisslinger, Dieter Steinhilber, Bettina Hofmann, Robert Fürst and Ewgenij Proschak

Molecules 2017, 22(1), 45; https://doi.org/10.3390/molecules22010045 - 29 Dec 2016

Cited by 19 | Viewed by 6227

Abstract

The arachidonic acid cascade is a key player in inflammation, and numerous well-established drugs interfere with this pathway. Previous studies have suggested that simultaneous inhibition of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH) results in synergistic anti-inflammatory effects. In this study, a novel prototype of a dual 5-LO/sEH inhibitor KM55 was rationally designed and synthesized. KM55 was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of KM55 in human whole blood and endothelial cells was investigated. KM55 potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood. KM55 was also tested in a cell function-based assay. The compound significantly inhibited the LPS-induced adhesion of leukocytes to endothelial cells by blocking leukocyte activation. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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Review

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1011 KiB

Open AccessReview

A Systematic Review of Computational Drug Discovery, Development, and Repurposing for Ebola Virus Disease Treatment

by James Schuler, Matthew L. Hudson, Diane Schwartz and Ram Samudrala

Molecules 2017, 22(10), 1777; https://doi.org/10.3390/molecules22101777 - 20 Oct 2017

Cited by 23 | Viewed by 9693

Abstract

Ebola virus disease (EVD) is a deadly global public health threat, with no currently approved treatments. Traditional drug discovery and development is too expensive and inefficient to react quickly to the threat. We review published research studies that utilize computational approaches to find or develop drugs that target the Ebola virus and synthesize its results. A variety of hypothesized and/or novel treatments are reported to have potential anti-Ebola activity. Approaches that utilize multi-targeting/polypharmacology have the most promise in treating EVD. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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1711 KiB

Open AccessReview

Anesthetic Agents of Plant Origin: A Review of Phytochemicals with Anesthetic Activity

by Hironori Tsuchiya

Molecules 2017, 22(8), 1369; https://doi.org/10.3390/molecules22081369 - 18 Aug 2017

Cited by 88 | Viewed by 15975

Abstract

The majority of currently used anesthetic agents are derived from or associated with natural products, especially plants, as evidenced by cocaine that was isolated from coca (Erythroxylum coca, Erythroxylaceae) and became a prototype of modern local anesthetics and by thymol and eugenol contained in thyme (Thymus vulgaris, Lamiaceae) and clove (Syzygium aromaticum, Myrtaceae), respectively, both of which are structurally and mechanistically similar to intravenous phenolic anesthetics. This paper reviews different classes of phytochemicals with the anesthetic activity and their characteristic molecular structures that could be lead compounds for anesthetics and anesthesia-related drugs. Phytochemicals in research papers published between 1996 and 2016 were retrieved from the point of view of well-known modes of anesthetic action, that is, the mechanistic interactions with Na⁺ channels, γ-aminobutyric acid type A receptors, N-methyl-d-aspartate receptors and lipid membranes. The searched phytochemicals include terpenoids, alkaloids and flavonoids because they have been frequently reported to possess local anesthetic, general anesthetic, antinociceptive, analgesic or sedative property. Clinical applicability of phytochemicals to local and general anesthesia is discussed by referring to animal in vivo experiments and human pre-clinical trials. This review will give structural suggestions for novel anesthetic agents of plant origin. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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10010 KiB

Open AccessReview

Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs

by Rona R. Ramsay and Keith F. Tipton

Molecules 2017, 22(7), 1192; https://doi.org/10.3390/molecules22071192 - 15 Jul 2017

Cited by 172 | Viewed by 26802

Abstract

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC₅₀ value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions. Full article

(This article belongs to the Special Issue Polypharmacology and Multitarget Drug Discovery)

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