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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: 25 January 2025 | Viewed by 9368

Special Issue Editor

Dr. Fedora Grande

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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.

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Published Papers (7 papers)

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Research

19 pages, 7480 KiB  
Article
Design, Development and Immunogenicity Study of a Multi-Epitope Vaccine Prototype Against SARS-CoV-2
by Mariyana Atanasova, Ivan Dimitrov, Nikola Ralchev, Aleksandar Markovski, Iliyan Manoylov, Silviya Bradyanova, Nikolina Mihaylova, Andrey Tchorbanov and Irini Doytchinova
Pharmaceuticals 2024, 17(11), 1498; https://doi.org/10.3390/ph17111498 - 7 Nov 2024
Viewed by 867
Abstract
Objectives: SARS-CoV-2 caused the COVID-19 pandemic, which overwhelmed global healthcare systems. Over 776 million COVID-19 cases and more than 7 million deaths were reported by WHO in September 2024. COVID-19 vaccination is crucial for preventing infection and controlling the pandemic. Here, we describe [...] Read more.
Objectives: SARS-CoV-2 caused the COVID-19 pandemic, which overwhelmed global healthcare systems. Over 776 million COVID-19 cases and more than 7 million deaths were reported by WHO in September 2024. COVID-19 vaccination is crucial for preventing infection and controlling the pandemic. Here, we describe the design and development of a next-generation multi-epitope vaccine for SARS-CoV-2, consisting of T cell epitopes. Methods: Immunoinformatic methods were used to derive models for the selection of MHC binders specific for the mouse strain used in this study among a set of human SARS-CoV-2 T cell epitopes identified in convalescent patients with COVID-19. The immunogenicity of the vaccine prototype was tested on humanized-ACE2 transgenic B6.Cg-Tg(K18-ACE2)2Prlmn/J mice by in vitro, in vivo, and ex vivo immunoassays. Results: Eleven binders (two from the Envelope (E) protein; two from the Membrane (M) protein; three from the Spike (S) protein; and four from the Nucleocapsid (N) protein) were synthesized and included in a multi-epitope vaccine prototype. The animals were immunized with a mix of predicted MHC-I, MHC-II, or MHC-I/MHC-II peptide epitopes in Complete Freund’s Adjuvant, and boosted with peptides in Incomplete Freund’s Adjuvant. Immunization with SARS-CoV-2 epitopes remodeled the lymphocyte profile. A weak humoral response and the significant production of IL-4 and IFN-γ from T cells were found after the vaccination of the animals. Conclusions: The multi-epitope vaccine prototype presented in this study demonstrates immunogenicity in mice and shows potential for human vaccine construction. 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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22 pages, 3966 KiB  
Article
Synthesis of New Thiazole-Privileged Chalcones as Tubulin Polymerization Inhibitors with Potential Anticancer Activities
by Hamada Hashem, Abdelfattah Hassan, Walid M. Abdelmagid, Ahmed G. K. Habib, Mohamed A. A. Abdel-Aal, Ali M. Elshamsy, Amr El Zawily, Ibrahim Taha Radwan, Stefan Bräse, Ahmed S. Abdel-Samea and Safwat M. Rabea
Pharmaceuticals 2024, 17(9), 1154; https://doi.org/10.3390/ph17091154 - 31 Aug 2024
Cited by 1 | Viewed by 899
Abstract
A series of novel thiazole-based chalcones were evaluated for their anticancer activity as potential tubulin polymerization inhibitors. In vitro anticancer screening for the thiazole derivatives 2a–2p exhibited broad-spectrum antitumor activity against various cancer cell lines particularly Ovar-3 and MDA-MB-468 cells with [...] Read more.
A series of novel thiazole-based chalcones were evaluated for their anticancer activity as potential tubulin polymerization inhibitors. In vitro anticancer screening for the thiazole derivatives 2a–2p exhibited broad-spectrum antitumor activity against various cancer cell lines particularly Ovar-3 and MDA-MB-468 cells with a GI50 range from 1.55 to 2.95 μΜ, respectively. Compound 2e demonstrated significant inhibition of tubulin polymerization, with an IC50 value of 7.78 μM compared to Combretastatin-A4 (CA-4), with an IC50 value of 4.93 μM. Molecular docking studies of compounds 2e, 2g, and 2h into tubulin further supported these findings, revealing that they bind effectively to the colchicine binding site, mirroring key interactions exhibited by CA-4. Computational predictions suggested favorable oral bioavailability and drug-likeness for these compounds, highlighting their potential for further development as chemotherapeutic agents. 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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16 pages, 4083 KiB  
Article
Small Structural Differences in Proline-Rich Decapeptides Have Specific Effects on Oxidative Stress-Induced Neurotoxicity and L-Arginine Generation by Arginosuccinate Synthase
by Carlos Alberto-Silva, Brenda Rufino da Silva, Julio Cezar Araujo da Silva, Felipe Assumpção da Cunha e Silva, Roberto Tadashi Kodama, Wilmar Dias da Silva, Maricilia Silva Costa and Fernanda Calheta Vieira Portaro
Pharmaceuticals 2024, 17(7), 931; https://doi.org/10.3390/ph17070931 - 11 Jul 2024
Viewed by 851
Abstract
Introduction. The proline-rich decapeptide 10c (Bj-PRO-10c; ENWPHPQIPP) from the Bothrops jararaca snake modulates argininosuccinate synthetase (AsS) activity to stimulate L-arginine metabolite production and neuroprotection in the SH-SY5Y cell line. The relationships between structure, interactions with AsS, and neuroprotection are little known. We evaluated [...] Read more.
Introduction. The proline-rich decapeptide 10c (Bj-PRO-10c; ENWPHPQIPP) from the Bothrops jararaca snake modulates argininosuccinate synthetase (AsS) activity to stimulate L-arginine metabolite production and neuroprotection in the SH-SY5Y cell line. The relationships between structure, interactions with AsS, and neuroprotection are little known. We evaluated the neuroprotective effects of Bj-PRO-10c and three other PROs (Bn-PRO-10a, <ENWPRPKIPP; Bn-PRO-10a-MK, <ENWPRPKIPPMK; and, Bn-PRO-10c, <ENWPRPKVPP) identified from Bitis nasicornis snake venom, with a high degree of similarity to Bj-PRO-10c, on oxidative stress-induced toxicity in neuronal PC12 cells and L-arginine metabolite generation via AsS activity regulation. Methods. Cell integrity, metabolic activity, reactive oxygen species (ROS) production, and arginase activity were examined after 4 h of PRO pre-treatment and 20 h of H2O2-induced damage. Results. Only Bn-PRO-10a-MK and Bn-PRO-10c restored cell integrity and arginase function under oxidative stress settings, but they did not reduce ROS or cell metabolism. The MK dipeptide in Bn-PRO-10a-MK and valine (V8) in Bn-PRO-10c are important to these effects when compared to Bn-PRO-10a. Bj-PRO-10c is not neuroprotective in PC12 cells, perhaps because of their limited NMDA-type glutamate receptor activity. The PROs interaction analysis on AsS activation can be rated as follows: Bj-PRO-10c > Bn-PRO-10c > Bn-PRO-10a-MK > Bn-PRO-10a. The structure of PROs and their correlations with enzyme activity revealed that histidine (H5) and glutamine (Q7) in Bj-PRO-10c potentiated their affinity for AsS. Conclusions. Our investigation provides the first insights into the structure and molecular interactions of PROs with AsS, which could possibly further their neuropharmacological applications. 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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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 1683
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 1308
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
Cited by 1 | Viewed by 1623
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 - 8 Dec 2023
Viewed by 1464
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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