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Pharmaceutics
Special Issues
Multi-Target Drug Design for Complex Diseases
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Multi-Target Drug Design for Complex Diseases

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (10 May 2022) | Viewed by 31049

Special Issue Editors

Dr. David Ramirez

E-Mail Website
Guest Editor
Departamento de Farmacología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
Interests: systems pharmacology; pharmacoinformatics; coputer-aided drug design
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ana Martínez

E-Mail Website
Guest Editor
Centro de Investigaciones Biologicas (CIB-CSIC), Ramiro de Maetzu 9, Madrid, Spain
Interests: drug design; medicinal chemistry; neurodegenerative diseases; pharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are organizing a Special Issue of Pharmaceutics, an open access journal focusing on the science and technology of pharmaceutics and biopharmaceutics (IF. 4.421, ranks Q1 in the category of Pharmacology & Pharmacy). The plan is to publish this Special Issue on “Multi-Target Drug Design for Complex Diseases” in July 2021.

For this Special Issue, our main goal is to promote open and multi-disciplinary discussion about the current and promising strategies for multi-target drug design for complex diseases, including, among other topics, experimental and theoretical/computational approaches to identify novel targets, to expand the chemical space of bioactive compounds and to design new models of complex diseases. This Special Issue will accept articles from bioinformatics and molecular pharmacology to medicinal chemistry and clinical pharmacology oriented toward the development of pharmacological therapies for complex diseases. Contributions on these topics are welcome, including original research and reviews.

We look forward to receiving your manuscript submissions for this Special Issue.

Dr. David Ramírez
Prof. Dr. Ana Martínez
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. Pharmaceutics 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 2900 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

  • complex diseases
  • multi-target drug design
  • pharmacology
  • novel therapies
  • polypharmacology
  • medicinal chemistry

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Published Papers (7 papers)

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Research

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19 pages, 3639 KiB  
Article
Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach
by Yuliet Mazola, José C. E. Márquez Montesinos, David Ramírez, Leandro Zúñiga, Niels Decher, Ursula Ravens, Vladimir Yarov-Yarovoy and Wendy González
Pharmaceutics 2022, 14(7), 1356; https://doi.org/10.3390/pharmaceutics14071356 - 27 Jun 2022
Cited by 3 | Viewed by 2679
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed [...] Read more.
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that a combined blockade of Nav1.5 (and its current, INa) and Kv1.5 (and its current, IKur) ion channels yield a synergistic anti-arrhythmic effect without alterations in ventricles. We focused on Kv1.5 and Nav1.5 to search for structural similarities in their binding site (BS) for flecainide (a common blocker and widely prescribed AAD) as a first step for prospective rational multi-target directed ligand (MTDL) design strategies. We present a computational workflow for a flecainide BS comparison in a flecainide-Kv1.5 docking model and a solved structure of the flecainide-Nav1.5 complex. The workflow includes docking, molecular dynamics, BS characterization and pattern matching. We identified a common structural pattern in flecainide BS for these channels. The latter belongs to the central cavity and consists of a hydrophobic patch and a polar region, involving residues from the S6 helix and P-loop. Since the rational MTDL design for AF is still incipient, our findings could advance multi-target atrial-selective strategies for AF treatment. Full article
(This article belongs to the Special Issue Multi-Target Drug Design for Complex Diseases)
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19 pages, 53764 KiB  
Article
In Silico Searching for Alternative Lead Compounds to Treat Type 2 Diabetes through a QSAR and Molecular Dynamics Study
by Nicolás Cabrera, Sebastián A. Cuesta, José R. Mora, Luis Calle, Edgar A. Márquez, Roland Kaunas and José Luis Paz
Pharmaceutics 2022, 14(2), 232; https://doi.org/10.3390/pharmaceutics14020232 - 19 Jan 2022
Cited by 8 | Viewed by 3684
Abstract
Free fatty acid receptor 1 (FFA1) stimulates insulin secretion in pancreatic β-cells. An advantage of therapies that target FFA1 is their reduced risk of hypoglycemia relative to common type 2 diabetes treatments. In this work, quantitative structure–activity relationship (QSAR) approach was used to [...] Read more.
Free fatty acid receptor 1 (FFA1) stimulates insulin secretion in pancreatic β-cells. An advantage of therapies that target FFA1 is their reduced risk of hypoglycemia relative to common type 2 diabetes treatments. In this work, quantitative structure–activity relationship (QSAR) approach was used to construct models to identify possible FFA1 agonists by applying four different machine-learning algorithms. The best model (M2) meets the Tropsha’s test requirements and has the statistics parameters R2 = 0.843, Q2CV = 0.785, and Q2ext = 0.855. Also, coverage of 100% of the test set based on the applicability domain analysis was obtained. Furthermore, a deep analysis based on the ADME predictions, molecular docking, and molecular dynamics simulations was performed. The lipophilicity and the residue interactions were used as relevant criteria for selecting a candidate from the screening of the DiaNat and DrugBank databases. Finally, the FDA-approved drugs bilastine, bromfenac, and fenofibric acid are suggested as potential and lead FFA1 agonists. Full article
(This article belongs to the Special Issue Multi-Target Drug Design for Complex Diseases)
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31 pages, 8112 KiB  
Article
Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors
by Jaka Dernovšek, Živa Zajec, Martina Durcik, Lucija Peterlin Mašič, Martina Gobec, Nace Zidar and Tihomir Tomašič
Pharmaceutics 2021, 13(8), 1283; https://doi.org/10.3390/pharmaceutics13081283 - 17 Aug 2021
Cited by 17 | Viewed by 3885
Abstract
Heat shock protein 90 (Hsp90) is a chaperone responsible for the maturation of many cancer-related proteins, and is therefore an important target for the design of new anticancer agents. Several Hsp90 N-terminal domain inhibitors have been evaluated in clinical trials, but none have [...] Read more.
Heat shock protein 90 (Hsp90) is a chaperone responsible for the maturation of many cancer-related proteins, and is therefore an important target for the design of new anticancer agents. Several Hsp90 N-terminal domain inhibitors have been evaluated in clinical trials, but none have been approved as cancer therapies. This is partly due to induction of the heat shock response, which can be avoided using Hsp90 C-terminal-domain (CTD) inhibition. Several structural features have been shown to be useful in the design of Hsp90 CTD inhibitors, including an aromatic ring, a cationic center and the benzothiazole moiety. This study established a previously unknown link between these structural motifs. Using ligand-based design methodologies and structure-based pharmacophore models, a library of 29 benzothiazole-based Hsp90 CTD inhibitors was prepared, and their antiproliferative activities were evaluated in MCF-7 breast cancer cells. Several showed low-micromolar IC50, with the most potent being compounds 5g and 9i (IC50, 2.8 ± 0.1, 3.9 ± 0.1 μM, respectively). Based on these results, a ligand-based structure–activity relationship model was built, and molecular dynamics simulation was performed to elaborate the binding mode of compound 9i. Moreover, compound 9i showed degradation of Hsp90 client proteins and no induction of the heat shock response. Full article
(This article belongs to the Special Issue Multi-Target Drug Design for Complex Diseases)
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16 pages, 5264 KiB  
Article
Trimethoxylated Halogenated Chalcones as Dual Inhibitors of MAO-B and BACE-1 for the Treatment of Neurodegenerative Disorders
by Payyalot Koyiparambath Vishal, Jong Min Oh, Ahmed Khames, Mohamed A. Abdelgawad, Aathira Sujathan Nair, Lekshmi R. Nath, Nicola Gambacorta, Fulvio Ciriaco, Orazio Nicolotti, Hoon Kim and Bijo Mathew
Pharmaceutics 2021, 13(6), 850; https://doi.org/10.3390/pharmaceutics13060850 - 8 Jun 2021
Cited by 28 | Viewed by 3972
Abstract
Six halogenated trimethoxy chalcone derivatives (CH1–CH6) were synthesized and spectrally characterized. The compounds were further evaluated for their inhibitory potential against monoamine oxidases (MAOs) and β-secretase (BACE-1). Six compounds inhibited MAO-B more effectively than MAO-A, and the 2′,3′,4′-methoxy moiety in CH4–CH6 was more [...] Read more.
Six halogenated trimethoxy chalcone derivatives (CH1–CH6) were synthesized and spectrally characterized. The compounds were further evaluated for their inhibitory potential against monoamine oxidases (MAOs) and β-secretase (BACE-1). Six compounds inhibited MAO-B more effectively than MAO-A, and the 2′,3′,4′-methoxy moiety in CH4–CH6 was more effective for MAO-B inhibition than the 2′,4′,6′-methoxy moiety in CH1–CH3. Compound CH5 most potently inhibited MAO-B, with an IC50 value of 0.46 µM, followed by CH4 (IC50 = 0.84 µM). In 2′,3′,4′-methoxy derivatives (CH4-CH6), the order of inhibition was –Br in CH5 > -Cl in CH4 > -F in CH6 at the para-position in ring B of chalcone. CH4 and CH5 were selective for MAO-B, with selectivity index (SI) values of 15.1 and 31.3, respectively, over MAO-A. CH4 and CH5 moderately inhibited BACE-1 with IC50 values of 13.6 and 19.8 µM, respectively. When CH4 and CH5 were assessed for their cell viability studies on the normal African Green Monkey kidney cell line (VERO) using MTT assays, it was noted that both compounds were found to be safe, and only a slightly toxic effect was observed in concentrations above 200 µg/mL. CH4 and CH5 decreased reactive oxygen species (ROS) levels of VERO cells treated with H2O2, indicating both compounds retained protective effects on the cells by antioxidant activities. All compounds showed high blood brain barrier permeabilities analyzed by a parallel artificial membrane permeability assay (PAMPA). Molecular docking and ADME prediction of the lead compounds provided more insights into the rationale behind the binding and the CNS drug likeness. From non-test mutagenicity and cardiotoxicity studies, CH4 and CH5 were non-mutagenic and non-/weak-cardiotoxic. These results suggest that CH4 and CH5 could be considered candidates for the cure of neurological dysfunctions. Full article
(This article belongs to the Special Issue Multi-Target Drug Design for Complex Diseases)
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19 pages, 4543 KiB  
Article
Design and In Vitro Study of a Dual Drug-Loaded Delivery System Produced by Electrospinning for the Treatment of Acute Injuries of the Central Nervous System
by Luisa Stella Dolci, Rosaria Carmela Perone, Roberto Di Gesù, Mallesh Kurakula, Chiara Gualandi, Elisa Zironi, Teresa Gazzotti, Maria Teresa Tondo, Giampiero Pagliuca, Natalia Gostynska, Vito Antonio Baldassarro, Maura Cescatti, Luciana Giardino, Maria Letizia Focarete, Laura Calzà, Nadia Passerini and Maria Laura Bolognesi
Pharmaceutics 2021, 13(6), 848; https://doi.org/10.3390/pharmaceutics13060848 - 8 Jun 2021
Cited by 9 | Viewed by 3915
Abstract
Vascular and traumatic injuries of the central nervous system are recognized as global health priorities. A polypharmacology approach that is able to simultaneously target several injury factors by the combination of agents having synergistic effects appears to be promising. Herein, we designed a [...] Read more.
Vascular and traumatic injuries of the central nervous system are recognized as global health priorities. A polypharmacology approach that is able to simultaneously target several injury factors by the combination of agents having synergistic effects appears to be promising. Herein, we designed a polymeric delivery system loaded with two drugs, ibuprofen (Ibu) and thyroid hormone triiodothyronine (T3) to in vitro release the suitable amount of the anti-inflammation and the remyelination drug. As a production method, electrospinning technology was used. First, Ibu-loaded micro (diameter circa 0.95–1.20 µm) and nano (diameter circa 0.70 µm) fibers were produced using poly(l-lactide) PLLA and PLGA with different lactide/glycolide ratios (50:50, 75:25, and 85:15) to select the most suitable polymer and fiber diameter. Based on the in vitro release results and in-house knowledge, PLLA nanofibers (mean diameter = 580 ± 120 nm) loaded with both Ibu and T3 were then successfully produced by a co-axial electrospinning technique. The in vitro release studies demonstrated that the final Ibu/T3 PLLA system extended the release of both drugs for 14 days, providing the target sustained release. Finally, studies in cell cultures (RAW macrophages and neural stem cell-derived oligodendrocyte precursor cells—OPCs) demonstrated the anti-inflammatory and promyelinating efficacy of the dual drug-loaded delivery platform. Full article
(This article belongs to the Special Issue Multi-Target Drug Design for Complex Diseases)
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Review

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22 pages, 5157 KiB  
Review
New Drug Design Avenues Targeting Alzheimer’s Disease by Pharmacoinformatics-Aided Tools
by Lily Arrué, Alexandra Cigna-Méndez, Tábata Barbosa, Paola Borrego-Muñoz, Silvia Struve-Villalobos, Victoria Oviedo, Claudia Martínez-García, Alexis Sepúlveda-Lara, Natalia Millán, José C. E. Márquez Montesinos, Juana Muñoz, Paula A. Santana, Carlos Peña-Varas, George E. Barreto, Janneth González and David Ramírez
Pharmaceutics 2022, 14(9), 1914; https://doi.org/10.3390/pharmaceutics14091914 - 9 Sep 2022
Cited by 7 | Viewed by 4519
Abstract
Neurodegenerative diseases (NDD) have been of great interest to scientists for a long time due to their multifactorial character. Among these pathologies, Alzheimer’s disease (AD) is of special relevance, and despite the existence of approved drugs for its treatment, there is still no [...] Read more.
Neurodegenerative diseases (NDD) have been of great interest to scientists for a long time due to their multifactorial character. Among these pathologies, Alzheimer’s disease (AD) is of special relevance, and despite the existence of approved drugs for its treatment, there is still no efficient pharmacological therapy to stop, slow, or repair neurodegeneration. Existing drugs have certain disadvantages, such as lack of efficacy and side effects. Therefore, there is a real need to discover new drugs that can deal with this problem. However, as AD is multifactorial in nature with so many physiological pathways involved, the most effective approach to modulate more than one of them in a relevant manner and without undesirable consequences is through polypharmacology. In this field, there has been significant progress in recent years in terms of pharmacoinformatics tools that allow the discovery of bioactive molecules with polypharmacological profiles without the need to spend a long time and excessive resources on complex experimental designs, making the drug design and development pipeline more efficient. In this review, we present from different perspectives how pharmacoinformatics tools can be useful when drug design programs are designed to tackle complex diseases such as AD, highlighting essential concepts, showing the relevance of artificial intelligence and new trends, as well as different databases and software with their main results, emphasizing the importance of coupling wet and dry approaches in drug design and development processes. Full article
(This article belongs to the Special Issue Multi-Target Drug Design for Complex Diseases)
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50 pages, 35991 KiB  
Review
A Comprehensive Review about the Molecular Structure of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Insights into Natural Products against COVID-19
by Essa M. Saied, Yousra A. El-Maradny, Alaa A. Osman, Amira M. G. Darwish, Hebatallah H. Abo Nahas, Gniewko Niedbała, Magdalena Piekutowska, Mohamed A. Abdel-Rahman, Bassem A. Balbool and Ahmed M. Abdel-Azeem
Pharmaceutics 2021, 13(11), 1759; https://doi.org/10.3390/pharmaceutics13111759 - 21 Oct 2021
Cited by 49 | Viewed by 6852
Abstract
In 2019, the world suffered from the emergence of COVID-19 infection, one of the most difficult pandemics in recent history. Millions of confirmed deaths from this pandemic have been reported worldwide. This disaster was caused by SARS-CoV-2, which is the last discovered member [...] Read more.
In 2019, the world suffered from the emergence of COVID-19 infection, one of the most difficult pandemics in recent history. Millions of confirmed deaths from this pandemic have been reported worldwide. This disaster was caused by SARS-CoV-2, which is the last discovered member of the family of Coronaviridae. Various studies have shown that natural compounds have effective antiviral properties against coronaviruses by inhibiting multiple viral targets, including spike proteins and viral enzymes. This review presents the classification and a detailed explanation of the SARS-CoV-2 molecular characteristics and structure–function relationships. We present all currently available crystal structures of different SARS-CoV-2 proteins and emphasized on the crystal structure of different virus proteins and the binding modes of their ligands. This review also discusses the various therapeutic approaches for COVID-19 treatment and available vaccinations. In addition, we highlight and compare the existing data about natural compounds extracted from algae, fungi, plants, and scorpion venom that were used as antiviral agents against SARS-CoV-2 infection. Moreover, we discuss the repurposing of select approved therapeutic agents that have been used in the treatment of other viruses. Full article
(This article belongs to the Special Issue Multi-Target Drug Design for Complex Diseases)
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