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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 24504

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Dr. Dharmendra Kumar Yadav

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College of Pharmacy, Gachon University of Medicine and Science, Incheon City 21924, Korea
Interests: molecular modeling; drug design; computer-aided drug design dynamics simulation of biological networks; plasma medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It has been observed that small molecules have continuously played an important role in the discovery of novel drugs to treat various kinds of human diseases. The discovery and development of peptide/protein, toxin, and antibody-based drugs will significantly improve the biomedical efficiency of disease specific therapy. In the current drug discovery and development program, structural and mechanistic enzymology plays a crucial role by making enzymes potential drug targets. At present, in drug design, the prediction and elucidation of biomolecular targets is possible, although their interactions with other molecules and mechanisms of action are unknown. Topics such as bio- and chemo-informatics, small molecules, machine learning, peptide drugs, and modulators may help to improve the knowledge and development of new treatments. A discussion on the use of novel disease-specific proteins/peptides/toxins/antibodies, along with the currently available approved drugs, as combinatorial treatments is also encouraged in this context.

This thematic issue aims to summarize recent advances in the medicinal chemistry of small molecules, mechanisms of action, and their application in clinical practice to treat various kinds of human diseases. The scope of this thematic issue will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, and structure–activity relationships.

Subtopics: The subtopics may include, but are not limited to, the following:

Role of small molecules in the modulation of multidrug transporters in different diseases;
Drug resistance transporters in bacteria: hopes from plant-based inhibitors;
Advancement of medicinal chemistry to modulate mechanisms of intrinsic and extrinsic apoptosis, new forms of programmed cell death;
New natural/synthetic small molecule leads to treatment of human diseases;
Current developments in target-based drug discovery;
Application of modern drug-designing tools in small-molecule lead optimization;
Challenges in target-based new drug development;
Alternative therapeutics: novelty and hopes;
Bio- and chemo-informatics, small molecules, machine learning, peptide drugs and modulators, and peptidomimetic compounds applied to drug discovery
Vaccine development

Dr. Dharmendra Kumar Yadav
Guest Editor

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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.

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Keywords

drug targets
biomolecular structure and drug design
small molecules
peptide drugs
medicinal chemistry

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Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases in International Journal of Molecular Sciences (12 articles)

Published Papers (9 papers)

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Research

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17 pages, 4058 KiB

Open AccessArticle

Sirtuin 6 Regulates the Activation of the ATP/Purinergic Axis in Endothelial Cells

by Cecilia Astigiano, Francesco Piacente, Maria Elena Laugieri, Andrea Benzi, Christian A. Di Buduo, Carolina P. Miguel, Debora Soncini, Michele Cea, Antonella Antonelli, Mauro Magnani, Alessandra Balduini, Antonio De Flora and Santina Bruzzone

Int. J. Mol. Sci. 2023, 24(7), 6759; https://doi.org/10.3390/ijms24076759 - 4 Apr 2023

Cited by 4 | Viewed by 2352

Abstract

Sirtuin 6 (SIRT6) is a member of the mammalian NAD⁺-dependent deac(et)ylase sirtuin family. SIRT6’s anti-inflammatory roles are emerging increasingly often in different diseases and cell types, including endothelial cells. In this study, the role of SIRT6 in pro-inflammatory conditions was investigated by engineering human umbilical vein endothelial cells to overexpress SIRT6 (SIRT6+ HUVECs). Our results showed that SIRT6 overexpression affected the levels of adhesion molecules and sustained megakaryocyte proliferation and proplatelet formation. Interestingly, the pro-inflammatory activation of the ATP/purinergic axis was reduced in SIRT6+ HUVECs. Specifically, the TNFα-induced release of ATP in the extracellular space and the increase in pannexin-1 hemichannel expression, which mediates ATP efflux, were hampered in SIRT6+ cells. Instead, NAD⁺ release and Connexin43 expression were not modified by SIRT6 levels. Moreover, the Ca²⁺ influx in response to ATP and the expression of the purinergic receptor P2X7 were decreased in SIRT6+ HUVECs. Contrary to extracellular ATP, extracellular NAD⁺ did not evoke pro-inflammatory responses in HUVECs. Instead, NAD⁺ administration reduced endothelial cell proliferation and motility and counteracted the TNFα-induced angiogenesis. Altogether, our data reinforce the view of SIRT6 activation as an anti-inflammatory approach in vascular endothelium. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0)

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16 pages, 5116 KiB

Open AccessArticle

In Silico Investigation of the Human GTP Cyclohydrolase 1 Enzyme Reveals the Potential of Drug Repurposing Approaches towards the Discovery of Effective BH₄ Therapeutics

by Dania Hussein

Int. J. Mol. Sci. 2023, 24(2), 1210; https://doi.org/10.3390/ijms24021210 - 7 Jan 2023

Cited by 4 | Viewed by 2405

Abstract

The GTP cyclohydrolase 1 enzyme (GTPCH1) is the rate-limiting enzyme of the tetrahydrobiopterin (BH₄) biosynthetic pathway. Physiologically, BH₄ plays a crucial role as an essential cofactor for the production of catecholamine neurotransmitters, including epinephrine, norepinephrine and dopamine, as well as the gaseous signaling molecule, nitric oxide. Pathological levels of the cofactor have been reported in a number of disease states, such as inflammatory conditions, neuropathic pain and cancer. Targeting the GTPCH1 enzyme has great potential in the management of a number of disease pathologies associated with dysregulated BH₄ physiology. This study is an in silico investigation of the human GTPCH1 enzyme using virtual screening and molecular dynamic simulation to identify molecules that can be repurposed to therapeutically target the enzyme. A three-tier molecular docking protocol was employed in the virtual screening of a comprehensive library of over 7000 approved medications and nutraceuticals in order to identify hit compounds capable of binding to the GTPCH1 binding pocket with the highest affinity. Hit compounds were further verified by molecular dynamic simulation studies to provide a detailed insight regarding the stability and nature of the binding interaction. In this study, we identify a number of drugs and natural compounds with recognized anti-inflammatory, analgesic and cytotoxic effects, including the aminosalicylate olsalazine, the antiepileptic phenytoin catechol, and the phlorotannins phlorofucofuroeckol and eckol. Our results suggest that the therapeutic and clinical effects of hit compounds may be partially attributed to the inhibition of the GTPCH1 enzyme. Notably, this study offers an understanding of the off-target effects of a number of compounds and advocates the potential role of aminosalicylates in the regulation of BH₄ production in inflammatory disease states. It highlights an in silico drug repurposing approach to identify a potential means of safely targeting the BH₄ biosynthetic pathway using established therapeutic agents. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0)

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11 pages, 2193 KiB

Open AccessArticle

Structural Studies of Expressed tIK, Anti-Inflammatory Peptide

by Minseon Kim and Yongae Kim

Int. J. Mol. Sci. 2023, 24(1), 636; https://doi.org/10.3390/ijms24010636 - 30 Dec 2022

Viewed by 1689

Abstract

Cytokine imbalance is one of the causes of inflammation. Inflammation has yet to be adequately treated without side effects. Therefore, we tried to develop a peptide drug with minimal side effects. Peptide drugs have the advantage of being bio-friendly and bio-specific. In a previous study, three peptides with anti-inflammatory activity were derived based on a truncated IK (tIK) protein, which was a fragment of the IK protein with anti-inflammatory effects. The objective of this study was to optimize the process of expressing, isolating, and purifying the three peptides using bacterial strains and describe the process. Circular dichroism and solution state nuclear magnetic resonance spectroscopy were performed on the final purified high-purity peptide and its secondary structure was also identified. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0)

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19 pages, 3631 KiB

Open AccessArticle

Targeting Multiple Homeostasis-Maintaining Systems by Ionophore Nigericin Is a Novel Approach for Senolysis

by Pavel I. Deryabin, Alla N. Shatrova and Aleksandra V. Borodkina

Int. J. Mol. Sci. 2022, 23(22), 14251; https://doi.org/10.3390/ijms232214251 - 17 Nov 2022

Cited by 5 | Viewed by 2438

Abstract

Within the present study we proposed a novel approach for senolysis based on the simultaneous disturbance of the several homeostasis-maintaining systems in senescent cells including intracellular ionic balance, energy production and intracellular utilization of damaged products. Of note, we could not induce senolysis by applying ouabain, amiloride, valinomycin or NH₄Cl—compounds that modify each of these systems solely. However, we found that ionophore nigericin can disturb plasma membrane potential, intracellular pH, mitochondrial membrane potential and autophagy at once. By affecting all of the tested homeostasis-maintaining systems, nigericin induced senolytic action towards stromal and epithelial senescent cells of different origins. Moreover, the senolytic effect of nigericin was independent of the senescence-inducing stimuli. We uncovered that K⁺ efflux caused by nigericin initiated pyroptosis in senescent cells. According to our data, the higher sensitivity of senescent cells compared to the control ones towards nigericin-induced death was partially mediated by the lower intracellular K⁺ content in senescent cells and by their predisposition towards pyroptosis. Finally, we proposed an interval dosing strategy to minimize the negative effects of nigericin on the control cells and to achieve maximal senolytic effect. Hence, our data suggest ionophore nigericin as a new senotherapeutic compound for testing against age-related diseases. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0)

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27 pages, 71481 KiB

Open AccessArticle

Discovering and Targeting Dynamic Drugging Pockets of Oncogenic Proteins: The Role of Magnesium in Conformational Changes of the G12D Mutated Kirsten Rat Sarcoma-Guanosine Diphosphate Complex

by Zheyao Hu and Jordi Marti

Int. J. Mol. Sci. 2022, 23(22), 13865; https://doi.org/10.3390/ijms232213865 - 10 Nov 2022

Cited by 8 | Viewed by 2263

Abstract

KRAS-G12D mutations are the one of most frequent oncogenic drivers in human cancers. Unfortunately, no therapeutic agent directly targeting KRAS-G12D has been clinically approved yet, with such mutated species remaining undrugged. Notably, cofactor Mg

^{2 +}

is closely related to the function of [...] Read more.

^{2 +}

is closely related to the function of small GTPases, but no investigation has been conducted yet on Mg

^{2 +}

when associated with KRAS. Herein, through microsecond scale molecular dynamics simulations, we found that Mg

^{2 +}

plays a crucial role in the conformational changes of the KRAS-GDP complex. We located two brand new druggable dynamic pockets exclusive to KRAS-G12D. Using the structural characteristics of these two dynamic pockets, we designed in silico the inhibitor DBD15-21-22, which can specifically and tightly target the KRAS-G12D-GDP-Mg

^{2 +}

ternary complex. Overall, we provide two brand new druggable pockets located on KRAS-G12D and suitable strategies for its inhibition. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0)

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16 pages, 1671 KiB

Open AccessArticle

The Efficacy and Biopharmaceutical Properties of a Fixed-Dose Combination of Disulfiram and Benzyl Benzoate

by Maria Lajarin-Reinares, Elia Martinez-Esteve, Eloy Pena-Rodríguez, Mariona Cañellas-Santos, Sanja Bulut, Kostas Karabelas, Adam Clauss, Carles Nieto, Mireia Mallandrich and Francisco Fernandez-Campos

Int. J. Mol. Sci. 2022, 23(18), 10969; https://doi.org/10.3390/ijms231810969 - 19 Sep 2022

Cited by 6 | Viewed by 4425

Abstract

Scabies and hair lice are parasitic diseases that affect human skin and hair, respectively. The incidence and resistances of these infections are increasing. Tenutex^® (disulfiram and benzyl benzoate emulsion) is an alternative to standard insecticides to avoid resistances. The aim of the work is to evaluate the transdermal absorption and the in vitro efficacy against scabies and hair lice after different exposition times. Dermatomed human skin was used to assess the dermal absorption using a validated High Performance Liquid Chromatography (HPLC) method. HEK001 keratinocytes were used to evaluate the cytotoxicity of benzyl benzoate. Only benzyl benzoate was able to cross the skin, but it did not show cytotoxicity at any of the tested concentrations. The product efficacy was tested on Psoroptes ovis after direct contact and after administration on sheep skin explants at different contact times. Permethrin/malathion-resistant strains of Pediculus humanis capitis adults and eggs were directly exposed to Tenutex, and the vitality and hatchability, respectively, were evaluated. The anti-scabies study demonstrated that exposure for 6 or 24 h completely eradicated the parasite. The pediculicidal activity of Tenutex exhibited superior efficacy than standard treatment on resistant lice. The positive results obtained suggest that Tenutex^® is a good treatment option, especially in drug resistance situations. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0)

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18 pages, 5322 KiB

Open AccessArticle

4-Arylthiosemicarbazide Derivatives as Toxoplasmic Aromatic Amino Acid Hydroxylase Inhibitors and Anti-inflammatory Agents

by Adrian Bekier, Anna Brzostek, Agata Paneth, Bożena Dziadek, Jarosław Dziadek, Justyna Gatkowska and Katarzyna Dzitko

Int. J. Mol. Sci. 2022, 23(6), 3213; https://doi.org/10.3390/ijms23063213 - 16 Mar 2022

Cited by 7 | Viewed by 2401

Abstract

Approximately one-third of the human population is infected with the intracellular cosmopolitan protozoan Toxoplasma gondii (Tg), and a specific treatment for this parasite is still needed. Additionally, the increasing resistance of Tg to drugs has become a challenge for numerous research centers. The high selectivity of a compound toward the protozoan, along with low cytotoxicity toward the host cells, form the basis for further research, which aims at determining the molecular targets of the active compounds. Thiosemicarbazide derivatives are biologically active organic compounds. Previous studies on the initial preselection of 58 new 4-arylthiosemicarbazide derivatives in terms of their anti-Tg activity and selectivity made it possible to select two promising derivatives for further research. One of the important amino acids involved in the proliferation of Tg and the formation of parasitophorous vacuoles is tyrosine, which is converted by two unique aromatic amino acid hydroxylases to levodopa. Enzymatic studies with two derivatives (R: para-nitro and meta-iodo) and recombinant aromatic amino acid hydroxylase (AAHs) obtained in the E. coli expression system were performed, and the results indicated that toxoplasmic AAHs are a molecular target for 4-arylthiosemicarbazide derivatives. Moreover, the drug affinity responsive target stability assay also confirmed that the selected compounds bind to AAHs. Additionally, the anti-inflammatory activity of these derivatives was tested using THP1-Blue™ NF-κB reporter cells due to the similarity of the thiosemicarbazide scaffold to thiosemicarbazone, both of which are known NF-κB pathway inhibitors. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0)

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18 pages, 10341 KiB

Open AccessArticle

Biochemical Characterization of New Gemifloxacin Schiff Base (GMFX-o-phdn) Metal Complexes and Evaluation of Their Antimicrobial Activity against Some Phyto- or Human Pathogens

by Hazem S. Elshafie, Sadeek A. Sadeek, Ippolito Camele and Amira A. Mohamed

Int. J. Mol. Sci. 2022, 23(4), 2110; https://doi.org/10.3390/ijms23042110 - 14 Feb 2022

Cited by 41 | Viewed by 2209

Abstract

Four novel ligand-metal complexes were synthesized through the reaction of Fe(III), pleaseCo(II), Zn(II), and Zr(IV) with Schiff base gemifloxacin reacted with ortho-phenylenediamine (GMFX-o-phdn) to investigate their biological activities. Elemental analysis, FT-IR, ¹H NMR, UV-visible, molar conductance, melting points, magnetic susceptibility, and thermal analyses have been carried out for insuring the chelation process. The antimicrobial activity was carried out against Monilinia fructicola, Aspergillus flavus, Penicillium italicum, Botrytis cinerea, Escherichia coli, Bacillus cereus, Pseudomonas fluorescens, and P. aeruginosa. The radical scavenging activity (RSA%) was in vitro evaluated using ABTS method. FT-IR spectra indicated that GMFX-o-phdn chelated with metal ions as a tetradentate through oxygen of carboxylate group and nitrogen of azomethine group. The data of infrared, ¹H NMR, and molar conductivity indicate that GMFX–o-phdn reacted as neutral tetra dentate ligand (N₂O₂) with metal ions through the two oxygen atoms of the carboxylic group (oxygen containing negative charge) and two nitrogen atoms of azomethine group (each nitrogen containing a lone pair of electrons) (the absent of peak corresponding to ν(COOH) at 1715 cm⁻¹, the shift of azomethine group peak from 1633 cm⁻¹ to around 1570 cm⁻¹, the signal at 11 ppm of COOH and the presence of the chloride ions outside the complex sphere). Thermal analyses (TG-DTG/DTA) exhibited that the decaying of the metal complexes exists in three steps with the final residue metal oxide. The obtained data from DTA curves reflect that the degradation processes were exothermic or endothermic. Results showed that some of the studied complexes exhibited promising antifungal activity against most of the tested fungal pathogens, whereas they showed higher antibacterial activity against E. coli and B. cereus and low activity against P. fluorescens and P. aeruginosa. In addition, GMFX-o-phdn and its metal complexes showed strong antioxidant effect. In particular, the parent ligand and Fe(III) complex showed greater antioxidant capacity at low tested concentrations than that of other metal complexes where their IC₅₀ were 169.7 and 164.6 µg/mL, respectively. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0)

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Review

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15 pages, 1349 KiB

Open AccessReview

Potential Roles of Selectins in Periodontal Diseases and Associated Systemic Diseases: Could They Be Targets for Immunotherapy?

by Mei Zhong, Jiangyong Huang, Zhe Wu, Kok-Gan Chan, Lijing Wang, Jiang Li, Learn-Han Lee and Jodi Woan-Fei Law

Int. J. Mol. Sci. 2022, 23(22), 14280; https://doi.org/10.3390/ijms232214280 - 18 Nov 2022

Cited by 6 | Viewed by 3168

Abstract

Periodontal diseases are predisposing factors to the development of many systemic disorders, which is often initiated via leukocyte infiltration and vascular inflammation. These diseases could significantly affect human health and quality of life. Hence, it is vital to explore effective therapies to prevent disease progression. Periodontitis, which is characterized by gingival bleeding, disruption of the gingival capillary’s integrity, and irreversible destruction of the periodontal supporting bone, appears to be caused by overexpression of selectins in periodontal tissues. Selectins (P-, L-, and E-selectins) are vital members of adhesion molecules regulating inflammatory and immune responses. They are mainly located in platelets, leukocytes, and endothelial cells. Furthermore, selectins are involved in the immunopathogenesis of vascular inflammatory diseases, such as cardiovascular disease, diabetes, cancers, and so on, by mediating leukocyte recruitment, platelet activation, and alteration of endothelial barrier permeability. Therefore, selectins could be new immunotherapeutic targets for periodontal disorders and their associated systemic diseases since they play a crucial role in immune regulation and endothelium dysfunction. However, the research on selectins and their association with periodontal and systemic diseases remains limited. This review aims to discuss the critical roles of selectins in periodontitis and associated systemic disorders and highlights the potential of selectins as therapeutic targets. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0)

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