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Small Molecules in Drug Discovery and Pharmacology

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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 (30 November 2021) | Viewed by 29614

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Special Issue Editors

Dr. Letizia Giampietro

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Guest Editor

Department of Pharmacy, University “G. D’Annunzio”, Chieti-Pescara, Italy
Interests: bioactive compounds; PPAR agonists; anticancer activity; neuroprotection; antioxidants; aromatase inhibitors; NOS; small molecules; medicinal chemistry; organic synthesis
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Dr. Claudio Ferrante

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Guest Editor

Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini, Italy
Interests: pharma-toxicological and phytochemical evaluation of medicinal plant and herbal extract activity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Small molecules are low-molecular-weight compounds that regulate many biological targets, such as enzymes, channels, and receptors. These little molecules can include lipids, monosaccharides, second messengers, natural products, metabolites, metal ions, new synthesized compounds, and drugs and other xenobiotics. In medicinal chemistry, chemical biology, and pharmacology, small molecules can be used as chemical tools.

Today, most marketed drugs are small molecules and most are delivered orally. Due to their small size, small molecules have the advantage of being able to pass through cell membranes to reach targets in the cell. The identification of new small molecules, either synthetic or naturally occurring, represents an interesting approach to the development of new therapeutic agents.

The aim of this Special Issue is to highlight recent research in different therapeutic areas of “Small Molecules in Drug Discovery and Pharmacology”. In particular, this Special Issue aims to present the most recent advances in the design, synthesis, and pharmacological evaluation of small molecules.

This Special Issue will accept original research papers and high-quality reviews on:

- the design, synthesis, and identification of new small molecules;

- the pharmacological evaluation of small molecules endowed with biological activity;

- the isolation and identification of small molecules from natural sources; and

- the evaluation of molecular mechanisms and biological targets of new synthesized small molecules.

We hope that this Special Issue will make an important contribution to our knowledge of the importance of small molecules in drug discovery and pharmacology.

Dr. Letizia Giampietro
Prof. Dr. Claudio Ferrante
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. 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

small molecules
natural products
drug design
synthetic strategies
structure–activity relationship
docking studies
drug delivery
in vivo, in vitro, and ex vivo evaluation
biological activity

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Published Papers (8 papers)

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Research

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10 pages, 1622 KiB

Open AccessArticle

The Small Molecule PPARγ Agonist GL516 Induces Feeding-Stimulatory Effects in Hypothalamus Cells Hypo-E22 and Isolated Hypothalami

by Annalisa Chiavaroli, Viviana di Giacomo, Barbara De Filippis, Amelia Cataldi, Claudio Ferrante and Letizia Giampietro

Molecules 2022, 27(15), 4882; https://doi.org/10.3390/molecules27154882 - 30 Jul 2022

Cited by 1 | Viewed by 2362

Abstract

PPARγ agonists are implicated in the regulation of diabetes and metabolic syndrome and have therapeutic potential in brain disorders. PPARγ modulates appetite through its central effects, especially on the hypothalamic arcuate nucleus (ARC). Previous studies demonstrated that the small molecule GL516 is a PPARγ agonist able to reduce oxidative stress and apoptosis with a potential neuroprotective role. Herein, we investigated the effects of GL516, in vitro and ex vivo, on the levels of hypothalamic dopamine (DA) and serotonin (5-HT). The gene expressions of neuropeptide Y, CART, AgRP, and POMC, which play master roles in the neuroendocrine regulation of feeding behavior and energy balance, were also evaluated. HypoE22 cells were treated with H₂O₂ (300 μM) for 2 h e 30’ and with different concentrations of GL516 (1 nM-100 µM). The cell viability was evaluated after 24 and 48 h of culturing using the MTT test. DA and 5-HT levels in the HypoE22 cell supernatants were analyzed through HPLC; an ex vivo study on isolated hypothalamic specimens challenged with scalar concentrations of GL516 (1–100 µM) and with pioglitazone (10 µM) was carried out. The gene expressions of CART, NPY, AgRP, and POMC were also determined by a quantitative real-time PCR. The results obtained showed that GL516 was able to reduce DA and 5-HT turnover; moreover, it was effective in stimulating NPY and AgRP gene expressions with a concomitant reduction in CART and POMC gene expressions. These results highlight the capability of GL516 to modulate neuropeptide pathways deeply involved in appetite control suggesting an orexigenic effect. These findings emphasize the potential use of GL516 as a promising candidate for therapeutical applications in neurodegenerative diseases associated with the reduction in food intake and stimulation of catabolic pathways. Full article

(This article belongs to the Special Issue Small Molecules in Drug Discovery and Pharmacology)

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20 pages, 2440 KiB

Open AccessArticle

A New Series of Aryloxyacetic Acids Endowed with Multi-Target Activity towards Peroxisome Proliferator-Activated Receptors (PPARs), Fatty Acid Amide Hydrolase (FAAH), and Acetylcholinesterase (AChE)

by Rosalba Leuci, Leonardo Brunetti, Antonio Laghezza, Luca Piemontese, Antonio Carrieri, Leonardo Pisani, Paolo Tortorella, Marco Catto and Fulvio Loiodice

Molecules 2022, 27(3), 958; https://doi.org/10.3390/molecules27030958 - 31 Jan 2022

Cited by 11 | Viewed by 2540

Abstract

A new series of aryloxyacetic acids was prepared and tested as peroxisome proliferator-activated receptors (PPARs) agonists and fatty acid amide hydrolase (FAAH) inhibitors. Some compounds exhibited an interesting dual activity that has been recently proposed as a new potential therapeutic strategy for the treatment of Alzheimer’s disease (AD). AD is a multifactorial pathology, hence multi-target agents are currently one of the main lines of research for the therapy and prevention of this disease. Given that cholinesterases represent one of the most common targets of recent research, we decided to also evaluate the effects of our compounds on the inhibition of these specific enzymes. Interestingly, two of these compounds, (S)-5 and 6, showed moderate activity against acetylcholinesterase (AChE) and even some activity, although at high concentration, against Aβ peptide aggregation, thus demonstrating, in agreement with the preliminary dockings carried out on the different targets, the feasibility of a simultaneous multi-target activity towards PPARs, FAAH, and AChE. As far as we know, these are the first examples of molecules endowed with this pharmacological profile that might represent a promising line of research for the identification of novel candidates for the treatment of AD. Full article

(This article belongs to the Special Issue Small Molecules in Drug Discovery and Pharmacology)

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10 pages, 2888 KiB

Open AccessArticle

Halogen Bonding in Haspin-Halogenated Tubercidin Complexes: Molecular Dynamics and Quantum Chemical Calculations

by Yujing Zhou and Ming Wah Wong

Molecules 2022, 27(3), 706; https://doi.org/10.3390/molecules27030706 - 21 Jan 2022

Cited by 4 | Viewed by 2438

Abstract

Haspin, an atypical serine/threonine protein kinase, is a potential target for cancer therapy. 5-iodotubercidin (5-iTU), an adenosine derivative, has been identified as a potent Haspin inhibitor in vitro. In this paper, quantum chemical calculations and molecular dynamics (MD) simulations were employed to identify and quantitatively confirm the presence of halogen bonding (XB), specifically halogen∙∙∙π (aromatic) interaction between halogenated tubercidin ligands with Haspin. Consistent with previous theoretical finding, the site specificity of the XB binding over the ortho-carbon is identified in all cases. A systematic increase of the interaction energy down Group 17, based on both quantum chemical and MD results, supports the important role of halogen bonding in this series of inhibitors. The observed trend is consistent with the experimental observation of the trend of activity within the halogenated tubercidin ligands (F < Cl < Br < I). Furthermore, non-covalent interaction (NCI) plots show that cooperative non-covalent interactions, namely, hydrogen and halogen bonds, contribute to the binding of tubercidin ligands toward Haspin. The understanding of the role of halogen bonding interaction in the ligand–protein complexes may shed light on rational design of potent ligands in the future. Full article

(This article belongs to the Special Issue Small Molecules in Drug Discovery and Pharmacology)

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29 pages, 4521 KiB

Open AccessArticle

Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)

by Malihe Masomian, Salima Lalani and Chit Laa Poh

Molecules 2021, 26(21), 6576; https://doi.org/10.3390/molecules26216576 - 30 Oct 2021

Cited by 6 | Viewed by 2903

Abstract

Enterovirus 71 (EV-A71) is one of the predominant etiological agents of hand, foot and mouth disease (HMFD), which can cause severe central nervous system infections in young children. There is no clinically approved vaccine or antiviral agent against HFMD. The SP40 peptide, derived from the VP1 capsid of EV-A71, was reported to be a promising antiviral peptide that targeted the host receptor(s) involved in viral attachment or entry. So far, the mechanism of action of SP40 peptide is unknown. In this study, interactions between ten reported cell receptors of EV-A71 and the antiviral SP40 peptide were evaluated through molecular docking simulations, followed by in vitro receptor blocking with specific antibodies. The preferable binding region of each receptor to SP40 was predicted by global docking using HPEPDOCK and the cell receptor-SP40 peptide complexes were refined using FlexPepDock. Local molecular docking using GOLD (Genetic Optimization for Ligand Docking) showed that the SP40 peptide had the highest binding score to nucleolin followed by annexin A2, SCARB2 and human tryptophanyl-tRNA synthetase. The average GoldScore for 5 top-scoring models of human cyclophilin, fibronectin, human galectin, DC-SIGN and vimentin were almost similar. Analysis of the nucleolin-SP40 peptide complex showed that SP40 peptide binds to the RNA binding domains (RBDs) of nucleolin. Furthermore, receptor blocking by specific monoclonal antibody was performed for seven cell receptors of EV-A71 and the results showed that the blocking of nucleolin by anti-nucleolin alone conferred a 93% reduction in viral infectivity. Maximum viral inhibition (99.5%) occurred when SCARB2 was concurrently blocked with anti-SCARB2 and the SP40 peptide. This is the first report to reveal the mechanism of action of SP40 peptide in silico through molecular docking analysis. This study provides information on the possible binding site of SP40 peptide to EV-A71 cellular receptors. Such information could be useful to further validate the interaction of the SP40 peptide with nucleolin by site-directed mutagenesis of the nucleolin binding site. Full article

(This article belongs to the Special Issue Small Molecules in Drug Discovery and Pharmacology)

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12 pages, 1383 KiB

Open AccessArticle

Crocodylus porosus Gut Bacteria: A Possible Source of Novel Metabolites

by Naveed Ahmed Khan, Morhanavallee Soopramanien, Sutherland Kester Maciver, Tengku Shahrul Anuar, Kuppusamy Sagathevan and Ruqaiyyah Siddiqui

Molecules 2021, 26(16), 4999; https://doi.org/10.3390/molecules26164999 - 18 Aug 2021

Cited by 13 | Viewed by 2951

Abstract

Crocodiles are remarkable animals that have the ability to endure extremely harsh conditions and can survive up to a 100 years while being exposed to noxious agents that are detrimental to Homo sapiens. Besides their immunity, we postulate that the microbial gut flora of crocodiles may produce substances with protective effects. In this study, we isolated and characterized selected bacteria colonizing the gastrointestinal tract of Crocodylusporosus and demonstrated their inhibitory effects against three different cancerous cell lineages. Using liquid chromatography-mass spectrometry, several molecules were identified. For the first time, we report partial analyses of crocodile’s gut bacterial molecules. Full article

(This article belongs to the Special Issue Small Molecules in Drug Discovery and Pharmacology)

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12 pages, 1097 KiB

Open AccessArticle

5-Aza-2′-Deoxycytidine and Valproic Acid in Combination with CHIR99021 and A83-01 Induce Pluripotency Genes Expression in Human Adult Somatic Cells

by Alain Aguirre-Vázquez, Luis A. Salazar-Olivo, Xóchitl Flores-Ponce, Ana L. Arriaga-Guerrero, Dariela Garza-Rodríguez, María E. Camacho-Moll, Iván Velasco, Fabiola Castorena-Torres, Nidheesh Dadheech and Mario Bermúdez de León

Molecules 2021, 26(7), 1909; https://doi.org/10.3390/molecules26071909 - 29 Mar 2021

Cited by 6 | Viewed by 3444

Abstract

A generation of induced pluripotent stem cells (iPSC) by ectopic expression of OCT4, SOX2, KLF4, and c-MYC has established promising opportunities for stem cell research, drug discovery, and disease modeling. While this forced genetic expression represents an advantage, there will always be an issue with genomic instability and transient pluripotency genes reactivation that might preclude their clinical application. During the reprogramming process, a somatic cell must undergo several epigenetic modifications to induce groups of genes capable of reactivating the endogenous pluripotency core. Here, looking to increase the reprograming efficiency in somatic cells, we evaluated the effect of epigenetic molecules 5-aza-2′-deoxycytidine (5AZ) and valproic acid (VPA) and two small molecules reported as reprogramming enhancers, CHIR99021 and A83-01, on the expression of pluripotency genes and the methylation profile of the OCT4 promoter in a human dermal fibroblasts cell strain. The addition of this cocktail to culture medium increased the expression of OCT4, SOX2, and KLF4 expression by 2.1-fold, 8.5-fold, and 2-fold, respectively, with respect to controls; concomitantly, a reduction in methylated CpG sites in OCT4 promoter region was observed. The epigenetic cocktail also induced the expression of the metastasis-associated gene S100A4. However, the epigenetic cocktail did not induce the morphological changes characteristic of the reprogramming process. In summary, 5AZ, VPA, CHIR99021, and A83-01 induced the expression of OCT4 and SOX2, two critical genes for iPSC. Future studies will allow us to precise the mechanisms by which these compounds exert their reprogramming effects. Full article

(This article belongs to the Special Issue Small Molecules in Drug Discovery and Pharmacology)

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14 pages, 5493 KiB

Open AccessArticle

The Effects of Andrographolide on the Enhancement of Chondrogenesis and Osteogenesis in Human Suprapatellar Fat Pad Derived Mesenchymal Stem Cells

by Thitianan Kulsirirat, Sittisak Honsawek, Mariko Takeda-Morishita, Nuttanan Sinchaipanid, Wanvisa Udomsinprasert, Jiraporn Leanpolchareanchai and Korbtham Sathirakul

Molecules 2021, 26(7), 1831; https://doi.org/10.3390/molecules26071831 - 24 Mar 2021

Cited by 10 | Viewed by 2692

Abstract

Andrographolide is a labdane diterpenoid herb, which is isolated from the leaves of Andrographis paniculata, and widely used for its potential medical properties. However, there are no reports on the effects of andrographolide on the human suprapatellar fat pad of osteoarthritis patients. In the present study, our goal was to evaluate the innovative effects of andrographolide on viability and Tri-lineage differentiation of human mesenchymal stem cells from suprapatellar fat pad tissues. The results revealed that andrographolide had no cytotoxic effects when the concentration was less than 12.5 µM. Interestingly, andrographolide had significantly enhanced, dose dependent, osteogenesis and chondrogenesis as evidenced by a significantly intensified stain for Alizarin Red S, Toluidine Blue and Alcian Blue. Moreover, andrographolide can upregulate the expression of genes related to osteogenic and chondrogenic differentiation, including Runx2, OPN, Sox9, and Aggrecan in mesenchymal stem cells from human suprapatellar fat pad tissues. In contrast, andrographolide suppressed adipogenic differentiation as evidenced by significantly diminished Oil Red O staining and expression levels for adipogenic-specific genes for PPAR-γ2 and LPL. These findings confirm that andrographolide can specifically enhance osteogenesis and chondrogenesis of mesenchymal stem cells from human suprapatellar fat pad tissues. It has potential as a therapeutic agent derived from natural sources for regenerative medicine. Full article

(This article belongs to the Special Issue Small Molecules in Drug Discovery and Pharmacology)

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Review

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20 pages, 5164 KiB

Open AccessReview

Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives

by Stefano Lanzetti and Valentina Di Biase

Molecules 2022, 27(4), 1312; https://doi.org/10.3390/molecules27041312 - 15 Feb 2022

Cited by 18 | Viewed by 7554

Abstract

Voltage-gated calcium channels (VGCCs) are widely expressed in the brain, heart and vessels, smooth and skeletal muscle, as well as in endocrine cells. VGCCs mediate gene transcription, synaptic and neuronal structural plasticity, muscle contraction, the release of hormones and neurotransmitters, and membrane excitability. Therefore, it is not surprising that VGCC dysfunction results in severe pathologies, such as cardiovascular conditions, neurological and psychiatric disorders, altered glycemic levels, and abnormal smooth muscle tone. The latest research findings and clinical evidence increasingly show the critical role played by VGCCs in autism spectrum disorders, Parkinson’s disease, drug addiction, pain, and epilepsy. These findings outline the importance of developing selective calcium channel inhibitors and modulators to treat such prevailing conditions of the central nervous system. Several small molecules inhibiting calcium channels are currently used in clinical practice to successfully treat pain and cardiovascular conditions. However, the limited palette of molecules available and the emerging extent of VGCC pathophysiology require the development of additional drugs targeting these channels. Here, we provide an overview of the role of calcium channels in neurological disorders and discuss possible strategies to generate novel therapeutics. Full article

(This article belongs to the Special Issue Small Molecules in Drug Discovery and Pharmacology)

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