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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: 20 June 2024 | Viewed by 9259

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Dr. Susanna Nencetti

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Guest Editor

Associate Professor, Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Interests: medicinal chemistry; drug discovery; metalloenzyme inhibitors; neurodegenerative diseases; anticancer drugs; CNS agents; chemical synthesis; structure–activity relationship; natural products
Special Issues, Collections and Topics in MDPI journals

Dr. Lidia Ciccone

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Guest Editor

Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Interests: amyloid proteins; medicinal chemistry; degenerative diseases; drug design; X-ray crystallography; chemical synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drugs, both of natural and synthetic origin, interact with specific targets in the body to prevent or cure diseases/disorders.

Drug discovery starts with identifying an unsatisfied therapeutic need, including assessing the adequacy of the available therapies and researching a cure for new emerging diseases. Drug discovery and development is a highly expensive process that can be performed using different approaches: serendipity, screening a great number of molecules by high throughput screening (HTS), selective optimization of activity of drugs or natural products, repurposing known drugs, rational drug design and the synthesis of new molecular entities using the information derived from X-ray crystal structures and in silico modelling techniques. The use of these strategies can discover a result that will need an optimization process to improve its properties (such as increasing the affinity and selectivity for the target, non-toxicity, better bioavailability, etc.) to obtain a lead compound that will become a drug.

In this Special Issue,“Advances in Drug Discovery and Synthesis”, we focus on all aspects involved in the discovery of new drug candidates, e.g., the design and synthesis of biologically active molecules, new synthetic routes leading to the discovery and optimization of lead compounds, molecular modeling, bioinformatics, structure-based drug design, and crystal structure analysis. Research articles, comprehensive reviews, and short communications are welcome with the aim of collecting the most recent insights and results involving multidisciplinary approaches in the research of biologically active new molecules.

Dr. Susanna Nencetti
Dr. Lidia Ciccone
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

medicinal chemistry
drug discovery
design and synthesis of bioactive compounds
molecular modeling
X-ray crystallography
structure–activity relationships
structure-based drug design

Published Papers (7 papers)

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Research

13 pages, 2771 KiB

Open AccessArticle

Evaluation of the Antiviral Activity of Tabamide A and Its Structural Derivatives against Influenza Virus

by Soo Yong Shin, Joo Hee Lee, Jin Woo Kim, Wonkyun Ronny Im, Kongara Damodar, Hyung Ryeol Woo, Won-Keun Kim, Jeong Tae Lee and Sung Ho Jeon

Int. J. Mol. Sci. 2023, 24(24), 17296; https://doi.org/10.3390/ijms242417296 - 09 Dec 2023

Viewed by 938

Abstract

Influenza viruses cause severe endemic respiratory infections in both humans and animals worldwide. The emergence of drug-resistant viral strains requires the development of new influenza therapeutics. Tabamide A (TA0), a phenolic compound isolated from tobacco leaves, is known to have antiviral activity. We investigated whether synthetic TA0 and its derivatives exhibit anti-influenza virus activity. Analysis of structure–activity relationship revealed that two hydroxyl groups and a double bond between C7 and C8 in TA0 are crucial for maintaining its antiviral action. Among its derivatives, TA25 showed seven-fold higher activity than TA0. Administration of TA0 or TA25 effectively increased survival rate and reduced weight loss of virus-infected mice. TA25 appears to act early in the viral infection cycle by inhibiting viral mRNA synthesis on the template-negative strand. Thus, the anti-influenza virus activity of TA0 can be expanded by application of its synthetic derivatives, which may aid in the development of novel antiviral therapeutics. Full article

(This article belongs to the Special Issue Advances in Drug Discovery and Synthesis)

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24 pages, 4392 KiB

Open AccessArticle

The Application of MicroRNAs in Glaucoma Research: A Bibliometric and Visualized Analysis

by Ruqi Zhang, Yuanyuan Tao and Jufang Huang

Int. J. Mol. Sci. 2023, 24(20), 15377; https://doi.org/10.3390/ijms242015377 - 19 Oct 2023

Viewed by 1348

Abstract

Glaucoma is similar to a neurodegenerative disorder and leads to global irreversible loss of vision. Despite extensive research, the pathophysiological mechanisms of glaucoma remain unclear, and no complete cure has yet been identified for glaucoma. Recent studies have shown that microRNAs can serve as diagnostic biomarkers or therapeutic targets for glaucoma; however, there are few bibliometric studies that focus on using microRNAs in glaucoma research. Here, we have adopted a bibliometric analysis in the field of microRNAs in glaucoma research to manifest the current tendencies and research hotspots and to present a visual map of the past and emerging tendencies in this field. In this study, we retrieved publications in the Web of Science database that centered on this field between 2007 and 2022. Next, we used VOSviewer, CiteSpace, Scimago Graphica, and Microsoft Excel to present visual representations of a co-occurrence analysis, co-citation analysis, tendencies, hotspots, and the contributions of authors, institutions, journals, and countries/regions. The United States was the main contributor. Investigative Ophthalmology and Visual Science has published the most articles in this field. Over the past 15 years, there has been exponential growth in the number of publications and citations in this field across various countries, organizations, and authors. Thus, this study illustrates the current trends, hotspots, and emerging frontiers and provides new insight and guidance for searching for new diagnostic biomarkers and clinical trials for glaucoma in the future. Furthermore, international collaborations can also be used to broaden and deepen the field of microRNAs in glaucoma research. Full article

(This article belongs to the Special Issue Advances in Drug Discovery and Synthesis)

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18 pages, 3976 KiB

Open AccessArticle

New Benzamides as Multi-Targeted Compounds: A Study on Synthesis, AChE and BACE1 Inhibitory Activity and Molecular Docking

by Danuta Drozdowska, Dawid Maliszewski, Agnieszka Wróbel, Artur Ratkiewicz and Michał Sienkiewicz

Int. J. Mol. Sci. 2023, 24(19), 14901; https://doi.org/10.3390/ijms241914901 - 04 Oct 2023

Cited by 1 | Viewed by 985

Abstract

The synthesis of eleven new and previously undescribed benzamides was designed. These compounds were specifically projected as potential inhibitors of the enzymes acetylcholinesterase (AChE) and β-secretase (BACE1). N,N′-(1,4-phenylene)bis(3-methoxybenzamide) was most active against AChE, with an inhibitory concentration of AChE IC₅₀ = 0.056 µM, while the IC₅₀ for donepezil was 0.046 µM. This compound was also the most active against the BACE1 enzyme. The IC₅₀ value was 9.01 µM compared to that for quercetin, with IC₅₀ = 4.89 µM. Quantitative results identified this derivative to be the most promising. Molecular modeling was performed to elucidate the potential mechanism of action of this compound. Dynamic simulations showed that new ligands only had a limited stabilizing effect on AChE, but all clearly reduced the flexibility of the enzyme. It can, therefore, be concluded that a possible mechanism of inhibition increases the stiffness and decreases the flexibility of the enzyme, which obviously impedes its proper function. An analysis of the H-bonding patterns suggests a different mechanism (from other ligands) when interacting the most active derivative with the enzyme. Full article

(This article belongs to the Special Issue Advances in Drug Discovery and Synthesis)

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29 pages, 10559 KiB

Open AccessArticle

Synthesis, Molecular Docking, and Biological Evaluation of Novel Anthranilic Acid Hybrid and Its Diamides as Antispasmodics

by Miglena Milusheva, Vera Gledacheva, Iliyana Stefanova, Mehran Feizi-Dehnayebi, Rositsa Mihaylova, Paraskev Nedialkov, Emiliya Cherneva, Yulian Tumbarski, Slava Tsoneva, Mina Todorova and Stoyanka Nikolova

Int. J. Mol. Sci. 2023, 24(18), 13855; https://doi.org/10.3390/ijms241813855 - 08 Sep 2023

Cited by 13 | Viewed by 1282

Abstract

The present article focuses on the synthesis and biological evaluation of a novel anthranilic acid hybrid and its diamides as antispasmodics. Methods: Due to the predicted in silico methods spasmolytic activity, we synthesized a hybrid molecule of anthranilic acid and 2-(3-chlorophenyl)ethylamine. The obtained hybrid was then applied in acylation with different acyl chlorides. Using in silico analysis, pharmacodynamic profiles of the compounds were predicted. A thorough biological evaluation of the compounds was conducted assessing their in vitro antimicrobial, cytotoxic, anti-inflammatory activity, and ex vivo spasmolytic activity. Density functional theory (DFT) calculation, including geometry optimization, molecular electrostatic potential (MEP) surface, and HOMO-LUMO analysis for the synthesized compounds was conducted using the B3LYP/6–311G(d,p) method to explore the electronic behavior, reactive regions, and stability and chemical reactivity of the compounds. Furthermore, molecular docking simulation along with viscosity measurement indicated that the newly synthesized compounds interact with DNA via groove binding mode. The obtained results from all the experiments demonstrate that the hybrid molecule and its diamides inherit spasmolytic, antimicrobial, and anti-inflammatory capabilities, making them excellent candidates for future medications. Full article

(This article belongs to the Special Issue Advances in Drug Discovery and Synthesis)

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25 pages, 6664 KiB

Open AccessArticle

Anti-Diabetic Activity of Glycyrrhetinic Acid Derivatives FC-114 and FC-122: Scale-Up, In Silico, In Vitro, and In Vivo Studies

by Samuel Álvarez-Almazán, Luz Cassandra Solís-Domínguez, Paulina Duperou-Luna, Teresa Fuerte-Gómez, Martin González-Andrade, María E. Aranda-Barradas, Juan Francisco Palacios-Espinosa, Jaime Pérez-Villanueva, Félix Matadamas-Martínez, Susana Patricia Miranda-Castro, Crisóforo Mercado-Márquez and Francisco Cortés-Benítez

Int. J. Mol. Sci. 2023, 24(16), 12812; https://doi.org/10.3390/ijms241612812 - 15 Aug 2023

Cited by 2 | Viewed by 1615

Abstract

Type 2 diabetes (T2D) is one of the most common diseases and the 8th leading cause of death worldwide. Individuals with T2D are at risk for several health complications that reduce their life expectancy and quality of life. Although several drugs for treating T2D are currently available, many of them have reported side effects ranging from mild to severe. In this work, we present the synthesis in a gram-scale as well as the in silico and in vitro activity of two semisynthetic glycyrrhetinic acid (GA) derivatives (namely FC-114 and FC-122) against Protein Tyrosine Phosphatase 1B (PTP1B) and α-glucosidase enzymes. Furthermore, the in vitro cytotoxicity assay on Human Foreskin fibroblast and the in vivo acute oral toxicity was also conducted. The anti-diabetic activity was determined in streptozotocin-induced diabetic rats after oral administration with FC-114 or FC-122. Results showed that both GA derivatives have potent PTP1B inhibitory activity being FC-122, a dual PTP1B/α-glucosidase inhibitor that could increase insulin sensitivity and reduce intestinal glucose absorption. Molecular docking, molecular dynamics, and enzymatic kinetics studies revealed the inhibition mechanism of FC-122 against α-glucosidase. Both GA derivatives were safe and showed better anti-diabetic activity in vivo than the reference drug acarbose. Moreover, FC-114 improves insulin levels while decreasing LDL and total cholesterol levels without decreasing HDL cholesterol. Full article

(This article belongs to the Special Issue Advances in Drug Discovery and Synthesis)

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16 pages, 4178 KiB

Open AccessArticle

Small Molecules with Thiourea Skeleton Induce Ethylene Response in Arabidopsis

by Tomoyuki Koyama, Honami Zaizen, Ikuo Takahashi, Hidemitsu Nakamura, Masatoshi Nakajima and Tadao Asami

Int. J. Mol. Sci. 2023, 24(15), 12420; https://doi.org/10.3390/ijms241512420 - 04 Aug 2023

Viewed by 989

Abstract

Ethylene is the only gaseous plant hormone that regulates several aspects of plant growth, from seedling morphogenesis to fruit ripening and organ senescence. Ethylene also stimulates the germination of Striga hermonthica, a root parasitic weed that severely damages crops in sub-Saharan Africa. Thus, ethylene response stimulants can be used as weed and crop control agents. Ethylene and ethephon, an ethylene-releasing compound, are currently used as ethylene response inducers. However, since ethylene is a gas, which limits its practical application, we targeted the development of a solid ethylene response inducer that could overcome this disadvantage. We performed chemical screening using Arabidopsis thaliana “triple response” as an indicator of ethylene response. After screening, we selected a compound with a thiourea skeleton and named it ZKT1. We then synthesized various derivatives of ZKT1 and evaluated their ethylene-like activities in Arabidopsis. Some derivatives showed considerably higher activity than ZKT1, and their activity was comparable to that of 1-aminocyclopropane-1-carboxylate. Mode of action analysis using chemical inhibitors and ethylene signaling mutants revealed that ZKT1 derivatives activate the ethylene signaling pathway through interactions with its upstream components. These thiourea derivatives can potentially be potent crop-controlling chemicals. Full article

(This article belongs to the Special Issue Advances in Drug Discovery and Synthesis)

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29 pages, 4751 KiB

Open AccessArticle

Novel Tetrazole Derivatives Targeting Tubulin Endowed with Antiproliferative Activity against Glioblastoma Cells

by Laura Gallego-Yerga, Andrea Jazmín Chiliquinga and Rafael Peláez

Int. J. Mol. Sci. 2023, 24(13), 11093; https://doi.org/10.3390/ijms241311093 - 04 Jul 2023

Viewed by 1497

Abstract

Increasing awareness of the structure of microtubules has made tubulin a relevant target for the research of novel chemotherapies. Furthermore, the particularly high sensitivity of glioblastoma multiforme (GBM) cells to microtubule disruption could open new doors in the search for new anti-GBM treatments. However, the difficulties in developing potent anti-tubulin drugs endowed with improved pharmacokinetic properties necessitates the expansion of medicinal chemistry campaigns. The application of an ensemble pharmacophore screening methodology helped to optimize this process, leading to the development of a new tetrazole-based tubulin inhibitor. Considering this scaffold, we have synthesized a new family of tetrazole derivatives that achieved remarkable antimitotic effects against a broad panel of cancer cells, especially against GBM cells, showing high selectivity in comparison with non-tumor cells. The compounds also exerted high aqueous solubility and were demonstrated to not be substrates of efflux pumps, thus overcoming the main limitations that are usually associated with tubulin binding agents. Tubulin polymerization assays, immunofluorescence experiments, and flow cytometry studies demonstrated that the compounds target tubulin and arrest cells at the G2/M phase followed by induction of apoptosis. The docking experiments agreed with the proposed interactions at the colchicine site and explained the structure–activity relationships. Full article

(This article belongs to the Special Issue Advances in Drug Discovery and Synthesis)

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