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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (30 October 2023) | Viewed by 23949

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Prof. Dr. Sarkar M. Abe Kawsar

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Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong 4331, Bangladesh
Interests: antimicrobial; carbohydrates; chemoinformatics; chromatography; computational /medicinal chemistry; organic synthesis; nucleosides; spectroscopy; glycobiology; pharmacokinetics; docking; molecular dynamics; DFT calculations; nucleosides-based drugs; structure-activity relationship; natural products; protein analysis

Prof. Dr. Yasuhiro Ozeki

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School of Sciences, Yokohama City University, 22-2, Seto, Kanazawa-Ku, Yokohama 236-0027, Japan
Interests: glycobiology; lectins; marine invertebrates
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Carbohydrates and glycosides are naturally occurring biomolecules that play essential roles in various physiological processes. For many decades, carbohydrates have been the subject of extensive research studies because of their involvement in viral and bacterial infection processes, cell growth and proliferation, cell-cell communication, and immune responses. They are the source of metabolic energy supply and contribute to fine-tuning cell-cell interactions and other essential processes. Nucleosides have, in recent times, been used as the backbone for many drugs in the treatment of infectious diseases caused by HIV, Hepatitis B or C viruses, and the Herpes viruses. Moreover, nucleosides have immense clinical importance as medicinal agents because of their antiviral and anticancer activities; they have been the “drug of choice” to treat various viral diseases, such as Ebola, dengue, and Zika, etc. Nucleoside precursors and nucleoside analogs are important in treating viral respiratory pathologies, especially during the current COVID-19 pandemic.

From this perspective, this Special Issue aims to provide a broad survey of the most recent advances in carbohydrates, glycosides, and nucleosides chemistry. Original research articles or reviews that discuss new synthesis, methodologies for the synthesis, biological, computational research, and their applications in different fields are welcome.

Prof. Dr. Sarkar M. Abe Kawsar
Prof. Dr. Yasuhiro Ozeki
Guest Editors

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Keywords

biological
carbohydrates
computational
glycobiology
glycosides
ligand-drug interactions
nucleosides
synthesis

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Published Papers (9 papers)

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Research

18 pages, 3120 KiB

Open AccessArticle

Stereocontrolled Synthesis and Conformational Analysis of a Series of Disaccharides α,β-d-GlcA-(1→3)-α-L-Fuc

by Alexey G. Gerbst, Dmitry Z. Vinnitsky, Alexandra I. Tokatly, Andrey S. Dmitrenok, Vadim B. Krylov, Nadezhda E. Ustuzhanina and Nikolay E. Nifantiev

Molecules 2023, 28(22), 7571; https://doi.org/10.3390/molecules28227571 - 13 Nov 2023

Cited by 1 | Viewed by 1311

Abstract

D-Glucuronic acid is a fundamental building block of many biologically important polysaccharides, either in its non-substituted form or bearing a variety of substituents, among them sulfates. We have previously performed a study of the effects of exhaustive sulfation on the conformational behavior of β-gluronopyranosides. Herein, we report an investigation comparing α- and β-derivatives of this monosaccharide within the title disaccharides using NMR and quantum chemistry approaches. It was found that for α-linked disaccharides, the introduction of sulfates did not greatly affect their conformational behavior. However, for β-derivatives, considerable conformational changes were observed. In general, they resemble those that took place for the monosaccharides, except that NOESY experiments and calculations of intra-ring spin–spin coupling constants suggest the presence of a ¹S₅ conformer along with ³S₁ in the fully sulfated disaccharide. During the synthesis of model compounds, hydrogen bond-mediated aglycone delivery was used as an α-directing stereocontrol approach in the glucuronidation reaction. Full article

(This article belongs to the Special Issue Recent Advances in Carbohydrates, Glycosides, and Nucleosides for Biological and Computational Research)

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15 pages, 9714 KiB

Open AccessArticle

Studying the Mechanism of Interaction of Doxofylline with Human Lysozyme: A Biophysical and In Silico Approach

by Suliman Yousef Alomar

Molecules 2023, 28(8), 3462; https://doi.org/10.3390/molecules28083462 - 14 Apr 2023

Cited by 3 | Viewed by 1646

Abstract

In this study, multiple spectroscopic and computational methods were utilized to investigate the binding mechanism of doxofylline with lysozyme. The in vitro methods were used to obtain the binding kinetics and thermodynamics. UV–vis spectroscopy indicated the formation of complex between doxofylline and lysozyme. The Gibb’s free energy and binding constant from UV–vis data was obtained as −7.20 kcal M⁻¹ and 1.929 × 10⁵ M⁻¹, respectively. Doxofylline successfully quenched the fluorescence of lysozyme, confirming the formation of complex. The k_q and K_sv values for the quenching of lysozyme’s fluorescence by doxofylline were 5.74 × 10¹¹ M⁻¹ s⁻¹ and 3.32 × 10³ M⁻¹, respectively. These values signified a moderate binding affinity between doxofylline and lysozyme. In synchronous spectroscopy, red shifts were observed for indicating the changes in microenvironment of lysozyme following the binding of doxofylline. The secondary structural analysis was determined using circular dichroism (CD) which revealed an increase in % α-helical as a result of doxofylline interaction. The binding affinity and flexibility of lysozyme upon complexation have been revealed via molecular docking and molecular dynamic (MD) simulations, respectively. According to the many parameters of the MD simulation, the lysozyme–doxofylline complex was stable under physiological conditions. All during the simulation time, hydrogen bonds were continuously present. The MM-PBSA binding energy for lysozyme and doxofylline binding was found to be −30.55 kcal mol⁻¹. Full article

(This article belongs to the Special Issue Recent Advances in Carbohydrates, Glycosides, and Nucleosides for Biological and Computational Research)

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27 pages, 9768 KiB

Open AccessArticle

Computational Approaches for Identification of Potential Plant Bioactives as Novel G6PD Inhibitors Using Advanced Tools and Databases

by Rana M. Aldossari, Aarif Ali, Muneeb U. Rehman, Summya Rashid and Sheikh Bilal Ahmad

Molecules 2023, 28(7), 3018; https://doi.org/10.3390/molecules28073018 - 28 Mar 2023

Cited by 5 | Viewed by 1982

Abstract

In glucose metabolism, the pentose phosphate pathway (PPP) is the major metabolic pathway that plays a crucial role in cancer growth and metastasis. Although it has been pointed out that blockade of the PPP is a promising approach against cancer, in the clinical setting, effective anti-PPP agents are still not available. Dysfunction of the G6PD enzyme in this pathway leads to cancer development as this enzyme possesses oncogenic activity. In the present study, an attempt was made to identify bioactive compounds that can be developed as potential G6PD inhibitors. In the present study, 11 natural compounds and a controlled drug were taken. The physicochemical and toxicity properties of the compounds were determined via ADMET and ProTox-II analysis. In the present study, the findings of docking studies revealed that staurosporine was the most effective compound with the highest binding energy of −9.2 kcal/mol when docked against G6PD. Homology modeling revealed that 97.56% of the residues were occupied in the Ramachandran-favored region. The modeled protein gave a quality Z-score of −10.13 by ProSA tool. iMODS server provided significant insights into the mobility, stability and flexibility of the G6PD protein that described the collective functional protein motion. In the present study, the physical and functional interactions between proteins were determined by STRING. CASTp server determined the topological and geometric properties of the G6PD protein. The findings of the present study revealed that staurosporine could be developed as a potential G6PD inhibitor; however, further in vivo and in vitro studies are needed for further validation of these results. Full article

(This article belongs to the Special Issue Recent Advances in Carbohydrates, Glycosides, and Nucleosides for Biological and Computational Research)

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25 pages, 5410 KiB

Open AccessArticle

Design, Synthesis, In Silico and POM Studies for the Identification of the Pharmacophore Sites of Benzylidene Derivatives

by Mohammad I. Hosen, Yousef E. Mukhrish, Ahmed Hussain Jawhari, Ismail Celik, Meryem Erol, Emad M. Abdallah, Mohammed Al-Ghorbani, Mohammed Baashen, Faisal A. Almalki, Hamid Laaroussi, Taibi Ben Hadda and Sarkar M. A. Kawsar

Molecules 2023, 28(6), 2613; https://doi.org/10.3390/molecules28062613 - 13 Mar 2023

Cited by 7 | Viewed by 2348

Abstract

Due to the uneven distribution of glycosidase enzyme expression across bacteria and fungi, glycoside derivatives of antimicrobial compounds provide prospective and promising antimicrobial materials. Therefore, herein, we report the synthesis and characterization of six novel methyl 4,6-O-benzylidene-α-d-glucopyranoside (MBG) derivatives (2–7). The structures were ascertained using spectroscopic techniques and elemental analyses. Antimicrobial tests (zone of inhibition, MIC and MBC) were carried out to determine their ability to inhibit the growth of different Gram-positive, Gram-negative bacteria and fungi. The highest antibacterial activity was recorded with compounds 4, 5, 6 and 7. The compounds with the most significant antifungal efficacy were 4, 5, 6 and 7. Based on the prediction of activity spectra for substances (PASS), compounds 4 and 7 have promising antimicrobial capacity. Molecular docking studies focused on fungal and bacterial proteins where derivatives 3 and 6 exhibited strong binding affinities. The molecular dynamics study revealed that the complexes formed by these derivatives with the proteins L,D-transpeptidase Ykud and endoglucanase from Aspergillus niger remained stable, both over time and in physiological conditions. Structure–activity relationships, including in vitro and in silico results, revealed that the acyl chains [lauroyl-(CH₃(CH₂)₁₀CO-), cinnamoyl-(C₆H₅CH=CHCO-)], in combination with sugar, were found to have the most potential against human and fungal pathogens. Synthetic, antimicrobial and pharmacokinetic studies revealed that MBG derivatives have good potential for antimicrobial activity, developing a therapeutic target for bacteria and fungi. Furthermore, the Petra/Osiris/Molinspiration (POM) study clearly indicated the presence of an important (O1^δ−----O2^δ−) antifungal pharmacophore site. This site can also be explored as a potential antiviral moiety. Full article

(This article belongs to the Special Issue Recent Advances in Carbohydrates, Glycosides, and Nucleosides for Biological and Computational Research)

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19 pages, 4455 KiB

Open AccessArticle

Rhamnopyranoside-Based Fatty Acid Esters as Antimicrobials: Synthesis, Spectral Characterization, PASS, Antimicrobial, and Molecular Docking Studies

by Abul Fazal Muhammad Sanaullah, Puja Devi, Takbir Hossain, Sulaiman Bin Sultan, Mohammad Mohib Ullah Badhon, Md. Emdad Hossain, Jamal Uddin, Md. Abdul Majed Patwary, Mohsin Kazi and Mohammed Mahbubul Matin

Molecules 2023, 28(3), 986; https://doi.org/10.3390/molecules28030986 - 18 Jan 2023

Cited by 6 | Viewed by 3072

Abstract

The most widely used and accessible monosaccharides have a number of stereogenic centers that have been hydroxylated and are challenging to chemically separate. As a result, the task of regioselective derivatization of such structures is particularly difficult. Considering this fact and to get novel rhamnopyranoside-based esters, DMAP-catalyzed di-O-stearoylation of methyl α-l-rhamnopyranoside (3) produced a mixture of 2,3-di-O- (4) and 3,4-di-O-stearates (5) (ratio 2:3) indicating the reactivity of the hydroxylated stereogenic centers of rhamnopyranoside as 3-OH > 4-OH > 2-OH. To get novel biologically active rhamnose esters, di-O-stearates 4 and 5 were converted into six 4-O- and 2-O-esters 6–11, which were fully characterized by FT-IR, ¹H, and ¹³C NMR spectral techniques. In vitro antimicrobial assays revealed that fully esterified rhamnopyranosides 6–11 with maximum lipophilic character showed better antifungal susceptibility than antibacterial activity. These experimental findings are similar to the results found from PASS analysis data. Furthermore, the pentanoyl derivative of 2,3-di-O-stearate (compound 6) showed better antifungal functionality against F. equiseti and A. flavus, which were found to be better than standard antibiotics. To validate the better antifungal results, molecular docking of the rhamnose esters 4–11 was performed with lanosterol 14α-demethylase (PDB ID: 3LD6), including the standard antifungal antibiotics ketoconazole and fluconazole. In this instance, the binding affinities of 10 (−7.6 kcal/mol), 9 (−7.5 kcal/mol), and 7 (−6.9 kcal/mol) were better and comparable to fluconazole (−7.3 kcal/mol), indicating the likelihood of their use as non-azole type antifungal drugs in the future. Full article

(This article belongs to the Special Issue Recent Advances in Carbohydrates, Glycosides, and Nucleosides for Biological and Computational Research)

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23 pages, 6169 KiB

Open AccessArticle

Efficient Antibacterial/Antifungal Activities: Synthesis, Molecular Docking, Molecular Dynamics, Pharmacokinetic, and Binding Free Energy of Galactopyranoside Derivatives

by Faez Ahmmed, Anis Ul Islam, Yousef E. Mukhrish, Youness El Bakri, Sajjad Ahmad, Yasuhiro Ozeki and Sarkar M. A. Kawsar

Molecules 2023, 28(1), 219; https://doi.org/10.3390/molecules28010219 - 26 Dec 2022

Cited by 16 | Viewed by 2651

Abstract

The chemistry and biochemistry of carbohydrate esters are essential parts of biochemical and medicinal research. A group of methyl β-d-galactopyranoside (β-MGP, 1) derivatives was acylated with 3-bromobenzoyl chloride and 4-bromobenzoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to obtain 6-O-substitution products, which were subsequently converted into 2,3,4-tri-O-acyl derivatives with different aliphatic and aromatic substituents. Spectroscopic and elemental data exploration of these derivatives confirmed their chemical structures. In vitro biological experiments against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) revealed ascending antifungal and antibacterial activities compared with their antiviral activities. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) experiments were performed for two derivatives, 3 and 9, based on their antibacterial activities. Most of these derivatives showed >780% inhibition of fungal mycelial growth. Density functional theory (DFT) was used to calculate the chemical descriptors and thermodynamic properties, whereas molecular docking was performed against antibacterial drug targets, including PDB: 4QDI, 5A5E, 7D27, 1ZJI, 3K8E, and 2MRW, and antifungal drug targets, such as PDB: 1EA1 and 1AI9, to identify potential drug candidates for microbial pathogens. A 100 ns molecular dynamics simulation study revealed stable conformation and binding patterns in a stimulating environment by their uniform RMSD, RMSF, SASA, H-bond, and RoG profiles. In silico pharmacokinetic and quantitative structure–activity relationship (QSAR) calculations (pIC₅₀ values 3.67~8.15) suggested that all the designed β-MGP derivatives exhibited promising results due to their improved kinetic properties with low aquatic and non-aquatic toxicities. These biological, structure–activity relationship (SAR) [lauroyl-(CH₃(CH₂)₁₀CO-) group was found to have potential], and in silico computational studies revealed that the newly synthesized MGP derivatives are potential antibacterial/antifungal candidates and can serve as therapeutic targets for human and plant pathogens. Full article

(This article belongs to the Special Issue Recent Advances in Carbohydrates, Glycosides, and Nucleosides for Biological and Computational Research)

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16 pages, 4066 KiB

Open AccessArticle

G-Quadruplex Aptamer-Ligand Characterization

by David Moreira, Daniela Leitão, Jéssica Lopes-Nunes, Tiago Santos, Joana Figueiredo, André Miranda, Daniela Alexandre, Cândida Tomaz, Jean-Louis Mergny and Carla Cruz

Molecules 2022, 27(20), 6781; https://doi.org/10.3390/molecules27206781 - 11 Oct 2022

Cited by 5 | Viewed by 3955

Abstract

In this work we explore the structure of a G-rich DNA aptamer termed AT11-L2 (TGGTGGTGGTTGTTGTTGGTGGTGGTGGT; derivative of AT11) by evaluating the formation and stability of G-quadruplex (G4) conformation under different experimental conditions such as KCl concentration, temperature, and upon binding with a variety of G4 ligands (360A, BRACO-19, PDS, PhenDC3, TMPyP4). We also determined whether nucleolin (NCL) can be a target of AT11-L2 G4. Firstly, we assessed by circular dichroism, UV and NMR spectroscopies the formation of G4 by AT11-L2. We observed that, for KCl concentrations of 65 mM or less, AT11-L2 adopts hybrid or multiple topologies. In contrast, a parallel topology predominates for buffer containing 100 mM of KCl. The T_m of AT11-L2 in 100 mM of KCl is 38.9 °C, proving the weak stability of this sequence. We also found that upon titration with two molar equivalents of 360A, BRACO-19 and PhenDC3, the G4 is strongly stabilized and its topology is maintained, while the addition of 3.5 molar equivalents of TMPyP4 promotes the disruption of G4. The K_D values between AT11-L2 G4, ligands and NCL were obtained by fluorescence titrations and are in the range of µM for ligand complexes and nM when adding NCL. In silico studies suggest that four ligands bind to the AT11-L2 G4 structure by stacking interactions, while the RBD1,2 domains of NCL interact preferentially with the thymines of AT11-L2 G4. Finally, AT11-L2 G4 co-localized with NCL in NCL-positive tongue squamous cell carcinoma cell line. Full article

(This article belongs to the Special Issue Recent Advances in Carbohydrates, Glycosides, and Nucleosides for Biological and Computational Research)

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19 pages, 6877 KiB

Open AccessArticle

Discovery of New VEGFR-2 Inhibitors: Design, Synthesis, Anti-Proliferative Evaluation, Docking, and MD Simulation Studies

by Eslam B. Elkaeed, Reda G. Yousef, Mohamed M. Khalifa, Albaraa Ibrahim, Ahmed B. M. Mehany, Ibraheem M. M. Gobaara, Bshra A. Alsfouk, Wagdy M. Eldehna, Ahmed M. Metwaly, Ibrahim H. Eissa and Mohamed Ayman El-Zahabi

Molecules 2022, 27(19), 6203; https://doi.org/10.3390/molecules27196203 - 21 Sep 2022

Cited by 19 | Viewed by 2372

Abstract

Four new nicotinamide-based derivatives were designed as antiangiogenic VEGFR-2 inhibitors. The congeners were synthesized possessing the pharmacophoric essential features to bind correctly with the VEGFR-2 active pocket. All members were evaluated for their cytotoxic and VEGFR-2 inhibitory potentialities. Compound 6 was the most potent showingIC₅₀ values of 9.3 ± 0.02 and 7.8 ± 0.025 µM against HCT-116 and HepG-2 cells, respectively, and IC₅₀ of 60.83 nM regarding VEGFR-2 enzyme inhibition. Compound 6 arrested the growth of HCT-116 cells at the pre-G1 and G2-M phases. Further, it induced both early and late apoptosis. Additionally, compound 6 caused a significant decrease in TNF-α and IL6 by 66.42% and 57.34%, respectively. The considered compounds had similar docking performances to that of sorafenib against the VEGFR-2 (PDB ID: 2OH4). The correct binding of compound 6 with VEGFR-2 was validated using MD simulations, and MM-GPSA calculations. Full article

(This article belongs to the Special Issue Recent Advances in Carbohydrates, Glycosides, and Nucleosides for Biological and Computational Research)

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24 pages, 7786 KiB

Open AccessArticle

Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation

by Alaa Elwan, Abdallah E. Abdallah, Hazem A. Mahdy, Mohammed A. Dahab, Mohammed S. Taghour, Eslam B. Elkaeed, Ahmed B. M. Mehany, Ahmed Nabeeh, Mohammed Adel, Aisha A. Alsfouk, Hazem Elkady and Ibrahim H. Eissa

Molecules 2022, 27(15), 5047; https://doi.org/10.3390/molecules27155047 - 8 Aug 2022

Cited by 38 | Viewed by 3087

Abstract

This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative of our previous work concerned with the development of VEGFR-2 inhibitor candidates. Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast cancer (MCF-7), colorectal carcinoma (HCT116), and hepatocellular carcinoma (HepG2). The synthesized compounds were also evaluated against VEGFR-2 kinase activity. The biological testing fallouts showed that compound 8d was more potent than standard sorafenib. Such compound showed IC₅₀ values of 3.43, 2.79, and 2.43 µM against the aforementioned cancer cell lines, respectively, compared to IC₅₀ values of 4.21, 5.30, and 3.40 µM reported for sorafenib. Compound 8d also was found to exert exceptional VEGFR-2 inhibition activity with an IC₅₀ value of 0.0554 μM compared to sorafenib (0.0782 μM). In addition, compound 8h revealed excellent cytotoxic effects with IC₅₀ values of 3.53, 2.94, and 2.76 µM against experienced cell lines, respectively. Furthermore, compounds 8a and 8e were found to inhibit VEGFR-2 kinase activity with IC₅₀ values of 0.0579 and 0.0741 μM, exceeding that of sorafenib. Compound 8d showed a significant apoptotic effect and arrested the HepG2 cells at the pre-G1 phase. In addition, it exerted a significant inhibition for TNF-α (90.54%) and of IL-6 (92.19%) compared to dexamethasone (93.15%). The molecular docking studies showed that the binding pattern of the new compounds to VEGFR-2 kinase was similar to that of sorafenib. Full article

(This article belongs to the Special Issue Recent Advances in Carbohydrates, Glycosides, and Nucleosides for Biological and Computational Research)

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