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Pharmaceuticals
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Advanced Strategies in Drug Design and Development of Small Molecules...
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Advanced Strategies in Drug Design and Development of Small Molecules as Therapeutic Agents

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 20 June 2024 | Viewed by 2997

Special Issue Editor

Dr. Fedora Grande

E-Mail Website
Guest Editor
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Ampl. Polifunzionale, Via P. Bucci, 87036 Arcavacata di Rende, Italy
Interests: drug design; small molecules; natural compounds; protein targeting; anticancer; antiviral; metabolic disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite the recent progress in drug research, there are still many concerns that need to be addressed in order to develop new and efficient therapeutics to overcome the side effects caused by conventional drugs.

Accordingly, the research of new active molecules is currently a compelling goal in medicinal chemistry. 

In recent decades, computational methods have become an essential and highly effective tool in drug design and development, allowing for significant advantages in terms of time and cost reduction and thus accelerating the entire drug discovery process.

This Special Issue aims to highlight current efforts towards innovative strategies for the design and development of small molecules, both of natural or synthetic origin, as drug candidates, with the aid of computational methods, such as molecular docking, virtual screening, pharmacophore modeling, QSAR modeling, and chemometric applications in forced degradation studies.

Its content will have to focus on advanced drug discovery approaches, including in silico identification of natural or synthetic therapeutic agents, structure–activity relationship definition, and the design of convenient synthetic strategies for new effective agents.

Reports on the biological and computational evaluation of newly synthesized small molecules as drug candidates or currently in clinical use will be considered as well.

Dr. Fedora Grande
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. Pharmaceuticals 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.

Published Papers (4 papers)

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Research

22 pages, 3686 KiB  
Article
Structure–Activity Relationship of Synthetic Linear KTS-Peptides Containing Meta-Aminobenzoic Acid as Antagonists of α1β1 Integrin with Anti-Angiogenic and Melanoma Anti-Tumor Activities
by Majdi Saleem Naamneh, Tatjana Momic, Michal Klazas, Julius Grosche, Johannes A. Eble, Cezary Marcinkiewicz, Netaly Khazanov, Hanoch Senderowitz, Amnon Hoffman, Chaim Gilon, Jehoshua Katzhendler and Philip Lazarovici
Pharmaceuticals 2024, 17(5), 549; https://doi.org/10.3390/ph17050549 - 24 Apr 2024
Viewed by 233
Abstract
To develop peptide drugs targeting integrin receptors, synthetic peptide ligands endowed with well-defined selective binding motifs are necessary. The snake venom KTS-containing disintegrins, which selectively block collagen α1β1 integrin, were used as lead compounds for the synthesis and structure–activity relationship of a series [...] Read more.
To develop peptide drugs targeting integrin receptors, synthetic peptide ligands endowed with well-defined selective binding motifs are necessary. The snake venom KTS-containing disintegrins, which selectively block collagen α1β1 integrin, were used as lead compounds for the synthesis and structure–activity relationship of a series of linear peptides containing the KTS-pharmacophore and alternating natural amino acids and 3-aminobenzoic acid (MABA). To ensure a better stiffness and metabolic stability, one, two and three MABA residues, were introduced around the KTS pharmacophore motif. Molecular dynamics simulations determined that the solution conformation of MABA peptide 4 is more compact, underwent larger conformational changes until convergence, and spent most of the time in a single cluster. The peptides’ binding affinity has been characterized by an enzyme linked immunosorbent assay in which the most potent peptide 4 inhibited with IC50 of 324 ± 8 µM and 550 ± 45 µM the binding of GST-α1-A domain to collagen IV fragment CB3, and the cell adhesion to collagen IV using α1-overexpressor cells, respectively. Docking studies and MM-GBSA calculations confirmed that peptide 4 binds a smaller region of the integrin near the collagen-binding site and penetrated deeper into the binding site near Trp1. Peptide 4 inhibited tube formation by endothelial cell migration in the Matrigel angiogenesis in vitro assay. Peptide 4 was acutely tolerated by mice, showed stability in human serum, decreased tumor volume and angiogenesis, and significantly increased the survival of mice injected with B16 melanoma cells. These findings propose that MABA-peptide 4 can further serve as an α1β1-integrin antagonist lead compound for further drug optimization in angiogenesis and cancer therapy. Full article
(This article belongs to the Special Issue Advanced Strategies in Drug Design and Development of Small Molecules as Therapeutic Agents)
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12 pages, 1683 KiB  
Article
Clindamycin Derivatives: Unveiling New Prospects as Potential Antitumor Agents
by Yiduo Jia, Yinmeng Zhang and Hong Zhu
Pharmaceuticals 2024, 17(3), 276; https://doi.org/10.3390/ph17030276 - 22 Feb 2024
Viewed by 668
Abstract
This study delves into the exploration of Clindamycin derivatives, specifically compounds 3 and 3e, to unveil their antitumor potential by employing a multidisciplinary approach. Screening a repertoire of 200 Clindamycin-associated targets pinpointed the Family A G-protein-coupled receptor as a prominent antitumor candidate. [...] Read more.
This study delves into the exploration of Clindamycin derivatives, specifically compounds 3 and 3e, to unveil their antitumor potential by employing a multidisciplinary approach. Screening a repertoire of 200 Clindamycin-associated targets pinpointed the Family A G-protein-coupled receptor as a prominent antitumor candidate. Subsequent analyses unearthed 16 pertinent antitumor proteins, with compound 3 exhibiting robust affinity towards a specific protein via stable hydrogen bonding. Molecular dynamics simulations underscored the adrenergic receptor β as a pivotal target, primarily situated in the plasma membrane and endoplasmic reticulum. These revelations hint towards compound 3’s potential to bolster natural defense mechanisms against tumors by modulating immune responses within the tumor microenvironment, thus paving the way for novel avenues in antitumor drug development. Furthermore, employing the MTT assay, we evaluated the anti-HepG2 cell activity of compounds 3 and 3e, with 5-fluorouracil serving as the control drug. Results revealed that compound 3 exhibited significant differences (p < 0.01) across all concentrations (2.5, 5, 10 μg/mL) compared to the control group, paralleled by the pronounced differences (p < 0.01) observed with 5-fluorouracil. Full article
(This article belongs to the Special Issue Advanced Strategies in Drug Design and Development of Small Molecules as Therapeutic Agents)
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15 pages, 3664 KiB  
Article
Anti-COVID Drugs (MMV COVID Box) as Leishmanicidal Agents: Unveiling New Therapeutic Horizons
by Atteneri López-Arencibia, Carlos J. Bethencourt-Estrella, Desirée San Nicolás-Hernández, Jacob Lorenzo-Morales and José E. Piñero
Pharmaceuticals 2024, 17(3), 266; https://doi.org/10.3390/ph17030266 - 20 Feb 2024
Viewed by 829
Abstract
Leishmaniasis, a neglected tropical disease, poses a significant global health challenge, necessitating the urgent development of innovative therapies. In this study, we aimed to identify compounds from the COVID Box with potential efficacy against two Leishmania species, laying the foundation for future chemical [...] Read more.
Leishmaniasis, a neglected tropical disease, poses a significant global health challenge, necessitating the urgent development of innovative therapies. In this study, we aimed to identify compounds from the COVID Box with potential efficacy against two Leishmania species, laying the foundation for future chemical development. Four promising molecules were discovered, demonstrating notable inhibitory effects against L. amazonensis and L. donovani. Our study revealed that bortezomib, almitrine, and terconazole induced a significant decrease in mitochondrial membrane potential, while the above compounds and ABT239 induced plasma permeability alterations, chromatin condensation, and reactive oxygen species accumulation, indicating early apoptosis in Leishmania amazonensis promastigotes, preventing inflammatory responses and tissue damage, thereby improving patient outcomes. Furthermore, ADME predictions revealed favorable pharmacokinetic profiles for all compounds, with bortezomib and ABT239 standing out as potential candidates. These compounds exhibited intestinal absorption, blood–brain barrier penetration (excluding bortezomib), and good drug-likeness for bortezomib and ABT239. Toxicity predictions for CYP-inhibition enzymes favored bortezomib as the safest candidate. In conclusion, our study identifies bortezomib as a promising aspirant for leishmaniasis treatment, demonstrating potent antiparasitic activity, favorable pharmacokinetics, and low toxicity. These findings emphasize the potential repurposing of existing drugs for neglected diseases and highlight the importance of the COVID Box in drug discovery against tropical diseases. Full article
(This article belongs to the Special Issue Advanced Strategies in Drug Design and Development of Small Molecules as Therapeutic Agents)
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19 pages, 4832 KiB  
Article
Identification of a Difluorinated Alkoxy Sulfonyl Chloride as a Novel Antitumor Agent for Hepatocellular Carcinoma through Activating Fumarate Hydratase Activity
by Jin Jin, Xujun Liang, Wu Bi, Ruijie Liu, Sai Zhang, Yi He, Qingming Xie, Shilei Liu, Ji-Chang Xiao and Pengfei Zhang
Pharmaceuticals 2023, 16(12), 1705; https://doi.org/10.3390/ph16121705 - 08 Dec 2023
Viewed by 950
Abstract
Fenofibrate is known as a lipid-lowering drug. Although previous studies have reported that fenofibrate exhibits potential antitumor activities, IC50 values of fenofibrate could be as high as 200 μM. Therefore, we investigated the antitumor activities of six synthesized fenofibrate derivatives. We discovered [...] Read more.
Fenofibrate is known as a lipid-lowering drug. Although previous studies have reported that fenofibrate exhibits potential antitumor activities, IC50 values of fenofibrate could be as high as 200 μM. Therefore, we investigated the antitumor activities of six synthesized fenofibrate derivatives. We discovered that one compound, SIOC-XJC-SF02, showed significant antiproliferative activity on human hepatocellular carcinoma (HCC) HCCLM3 cells and HepG2 cells (the IC50 values were 4.011 μM and 10.908 μM, respectively). We also found this compound could inhibit the migration of human HCC cells. Transmission electron microscope and flow cytometry assays demonstrated that this compound could induce apoptosis of human HCC cells. The potential binding sites of this compound acting on human HCC cells were identified by mass spectrometry-cellular thermal shift assay (MS-CETSA). Molecular docking, Western blot, and enzyme activity assay-validated binding sites in human HCC cells. The results showed that fumarate hydratase may be a potential binding site of this compound, exerting antitumor effects. A xenograft model in nude mice demonstrated the anti-liver cancer activity and the mechanism of action of this compound. These findings indicated that the antitumor effect of this compound may act via activating fumarate hydratase, and this compound may be a promising antitumor candidate for further investigation. Full article
(This article belongs to the Special Issue Advanced Strategies in Drug Design and Development of Small Molecules as Therapeutic Agents)
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