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18 pages, 4123 KiB

Open AccessArticle

Preparation of Thin Films Containing Modified Hydroxyapatite Particles and Phospholipids (DPPC) for Improved Properties of Biomaterials

by Monika Rojewska, Katarzyna Adamska, Justyna Kurnatowska, Andrzej Miklaszewski, Aneta Bartkowska and Krystyna Prochaska

Molecules 2023, 28(23), 7843; https://doi.org/10.3390/molecules28237843 - 29 Nov 2023

Viewed by 1092

Abstract

The main aims of thin biofilm synthesis are to either achieve a new form to promote the transport of drugs in oral delivery systems or as a coating to improve the biocompatibility of the implant’s surface. In this study, the Langmuir monolayer technique [...] Read more.

The main aims of thin biofilm synthesis are to either achieve a new form to promote the transport of drugs in oral delivery systems or as a coating to improve the biocompatibility of the implant’s surface. In this study, the Langmuir monolayer technique was employed to obtain films containing Mg-doped hydroxyapatite with 0.5%, 1.0%, and 1.5% Mg(II). The obtained modified HA particles were analysed via the FT-IR, XRD, DLS, and SEM methods. It was shown that the modified hydroxyapatite particles were able to form thin films at the air/water interface. BAM microscopy was employed to characterized the morphology of these films. In the next step, the mixed films were prepared using phospholipid (DPPC) molecules and modified hydroxyapatite particles (HA-Mg(II)). We expected that the presence of phospholipids (DPPC) in thin films improved the biocompatibility of the preparing films, while adding HA-Mg(II) particles will promote antibacterial properties and enhance osteogenesis processes. The films were prepared in two ways: (1) by mixing DPPC and HA-Mg (II) and spreading this solution onto the subphase, or (2) by forming DPPC films, dropping the HA-Mg (II) dispersion onto the phospholipid monolayer. Based on the obtained π–A isotherms, the surface parameters of the achieved thin films were estimated. It was observed that the HA-Mg(II) films can be stabilized with phospholipid molecules, and a more stable structure was obtained from films synthesied via method (2). Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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11 pages, 2901 KiB

Open AccessArticle

Determination and Kinetic Characterization of a New Potential Inhibitor for AmsI Protein Tyrosine Phosphatase from the Apple Pathogen Erwinia amylovora

by Simone Albani, Ivan Polsinelli, Luca Mazzei, Francesco Musiani and Stefano Benini

Molecules 2023, 28(23), 7774; https://doi.org/10.3390/molecules28237774 - 25 Nov 2023

Cited by 1 | Viewed by 1266

Abstract

Erwinia amylovora is a Gram-negative bacterium, responsible for the fire blight disease in Rosaceae plants. Its virulence is correlated with the production of an exopolysaccharide (EPS) called amylovoran, which protects the bacterium from the surrounding environment and helps its diffusion inside the host. [...] Read more.

Erwinia amylovora is a Gram-negative bacterium, responsible for the fire blight disease in Rosaceae plants. Its virulence is correlated with the production of an exopolysaccharide (EPS) called amylovoran, which protects the bacterium from the surrounding environment and helps its diffusion inside the host. Amylovoran biosynthesis relies on the expression of twelve genes clustered in the ams operon. One of these genes, amsI, encodes for a Low Molecular Weight Protein Tyrosine Phosphatase (LMW-PTP) called EaAmsI, which plays a key role in the regulation of the EPS production pathway. For this reason, EaAmsI was chosen in this work as a target for the development of new antibacterial agents against E. amylovora. To achieve this aim, a set of programs (DOCK6, OpenEye FRED) was selected to perform a virtual screening using a database of ca. 700 molecules. The six best-scoring compounds identified were tested in in vitro assays. A complete inhibition kinetic characterization carried out on the most promising molecule (n-Heptyl β-D-glucopyranoside, N7G) showed an inhibition constant of 7.8 ± 0.6 µM. This study represents an initial step towards the development of new EaAmsI inhibitors able to act as antibacterial agents against E. amylovora infections. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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12 pages, 3307 KiB

Open AccessArticle

The Green Tea Polyphenol Epigallocatechin-Gallate (EGCG) Interferes with Microcin E492 Amyloid Formation

by Paulina Aguilera, Camilo Berríos-Pastén, Marcelo Veloso, Matías Gálvez-Silva, Florian Turbant, Rosalba Lagos, Frank Wien, Veronique Arluison and Andrés E. Marcoleta

Molecules 2023, 28(21), 7262; https://doi.org/10.3390/molecules28217262 - 25 Oct 2023

Cited by 1 | Viewed by 1473

Abstract

Microcin E492 (MccE492) is an antimicrobial peptide and proposed virulence factor produced by some Klebsiella pneumoniae strains, which, under certain conditions, form amyloid fibers, leading to the loss of its antibacterial activity. Although this protein has been characterized as a model functional amyloid, [...] Read more.

Microcin E492 (MccE492) is an antimicrobial peptide and proposed virulence factor produced by some Klebsiella pneumoniae strains, which, under certain conditions, form amyloid fibers, leading to the loss of its antibacterial activity. Although this protein has been characterized as a model functional amyloid, the secondary structure transitions behind its formation, and the possible effect of molecules that inhibit this process, have not been investigated. In this study, we examined the ability of the green tea flavonoid epigallocatechin gallate (EGCG) to interfere with MccE492 amyloid formation. Aggregation kinetics followed by thioflavin T binding were used to monitor amyloid formation in the presence or absence of EGCG. Additionally, synchrotron radiation circular dichroism (SRCD) and transmission electron microscopy (TEM) were used to study the secondary structure, thermal stability, and morphology of microcin E492 fibers. Our results showed that EGCG significantly inhibited the formation of the MccE492 amyloid, resulting in mainly amorphous aggregates and small oligomers. However, these aggregates retained part of the β-sheet SRCD signal and a high resistance to heat denaturation, suggesting that the aggregation process is sequestered or deviated at some stage but not completely prevented. Thus, EGCG is an interesting inhibitor of the amyloid formation of MccE492 and other bacterial amyloids. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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19 pages, 4010 KiB

Open AccessArticle

A Novel and Efficient Phthalate Hydrolase from Acinetobacter sp. LUNF3: Molecular Cloning, Characterization and Catalytic Mechanism

by Shuanghu Fan, Jingjing Guo, Shaoyan Han, Haina Du, Zimeng Wang, Yajuan Fu, Hui Han, Xiaoqiang Hou and Weixuan Wang

Molecules 2023, 28(18), 6738; https://doi.org/10.3390/molecules28186738 - 21 Sep 2023

Cited by 3 | Viewed by 1463

Abstract

Phthalic acid esters (PAEs), which are widespread environmental contaminants, can be efficiently biodegraded, mediated by enzymes such as hydrolases. Despite great advances in the characterization of PAE hydrolases, which are the most important enzymes in the process of PAE degradation, their molecular catalytic [...] Read more.

Phthalic acid esters (PAEs), which are widespread environmental contaminants, can be efficiently biodegraded, mediated by enzymes such as hydrolases. Despite great advances in the characterization of PAE hydrolases, which are the most important enzymes in the process of PAE degradation, their molecular catalytic mechanism has rarely been systematically investigated. Acinetobacter sp. LUNF3, which was isolated from contaminated soil in this study, demonstrated excellent PAE degradation at 30 °C and pH 5.0–11.0. After sequencing and annotating the complete genome, the gene dphAN1, encoding a novel putative PAE hydrolase, was identified with the conserved motifs catalytic triad (Ser²⁰¹-Asp²⁹⁵-His³²⁵) and oxyanion hole (H¹²⁷GGG¹³⁰). DphAN1 can hydrolyze DEP (diethyl phthalate), DBP (dibutyl phthalate) and BBP (benzyl butyl phthalate). The high activity of DphAN1 was observed under a wide range of temperature (10–40 °C) and pH (6.0–9.0). Moreover, the metal ions (Fe²⁺, Mn²⁺, Cr²⁺ and Fe³⁺) and surfactant TritonX-100 significantly activated DphAN1, indicating a high adaptability and tolerance of DphAN1 to these chemicals. Molecular docking revealed the catalytic triad, oxyanion hole and other residues involved in binding DBP. The mutation of these residues reduced the activity of DphAN1, confirming their interaction with DBP. These results shed light on the catalytic mechanism of DphAN1 and may contribute to protein structural modification to improve catalytic efficiency in environment remediation. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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14 pages, 2754 KiB

Open AccessArticle

Modulation of NRF2/KEAP1-Mediated Oxidative Stress for Cancer Treatment by Natural Products Using Pharmacophore-Based Screening, Molecular Docking, and Molecular Dynamics Studies

by Abdulrahim A. Alzain, Rua M. Mukhtar, Nihal Abdelmoniem, Tagyedeen H. Shoaib, Wadah Osman, Marwa Alsulaimany, Ahmed K. B. Aljohani, Sara A. Almadani, Baiaan H. Alsaadi, Maryam M. Althubyani, Shaimaa G. A. Mohamed, Gamal A. Mohamed and Sabrin R. M. Ibrahim

Molecules 2023, 28(16), 6003; https://doi.org/10.3390/molecules28166003 - 10 Aug 2023

Cited by 5 | Viewed by 2493

Abstract

Oxidative stress plays a significant role in the development of cancer. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 offers a promising strategy to activate the Nrf2 antioxidant pathway, which is normally suppressed by the binding of Keap1 to Nrf2. This study [...] Read more.

Oxidative stress plays a significant role in the development of cancer. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 offers a promising strategy to activate the Nrf2 antioxidant pathway, which is normally suppressed by the binding of Keap1 to Nrf2. This study aimed to identify natural compounds capable of targeting the kelch domain of KEAP1 using structure-based drug design methods. A pharmacophore model was constructed based on the KEAP1-inhibitor complex, leading to the selection of 6178 compounds that matched the model. Subsequently, docking and MM/GBSA analyses were conducted, resulting in the identification of 10 compounds with superior binding energies compared to the reference compound. From these, three compounds (ZINC000002123788, ZINC000002111341, and ZINC000002125904) were chosen for further investigation. Ligand–residue interaction analysis revealed specific interactions between these compounds and key residues, indicating their stability within the binding site. ADMET analysis confirmed that the selected compounds possessed desirable drug-like properties. Furthermore, molecular dynamics simulations were performed, demonstrating the stability of the ligand–protein complexes over a 100 ns duration. These findings underscore the potential of the selected natural compounds as agents targeting KEAP1 and provide valuable insights for future experimental studies. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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20 pages, 6011 KiB

Open AccessArticle

The Reaction Mechanism of Loganic Acid Methyltransferase: A Molecular Dynamics Simulation and Quantum Mechanics Study

by Mateusz Jędrzejewski, Łukasz Szeleszczuk and Dariusz Maciej Pisklak

Molecules 2023, 28(15), 5767; https://doi.org/10.3390/molecules28155767 - 30 Jul 2023

Cited by 2 | Viewed by 1574

Abstract

In this work, the catalytic mechanism of loganic acid methyltransferase was characterized at the molecular level. This enzyme is responsible for the biosynthesis of loganin, which is a precursor for a wide range of biologically active compounds. Due to the lack of detailed [...] Read more.

In this work, the catalytic mechanism of loganic acid methyltransferase was characterized at the molecular level. This enzyme is responsible for the biosynthesis of loganin, which is a precursor for a wide range of biologically active compounds. Due to the lack of detailed knowledge about this process, the aim of this study was the analysis of the structure and activity of loganic acid methyltransferase. Using molecular dynamics (MD) simulations, the native structure of the complex was reconstructed, and the key interactions between the substrate and loganic acid methyltransferase were investigated. Subsequently, the structures obtained from the simulations were used for quantum chemical (QM) calculations. The QM calculations allowed for the exploration of the energetic aspects of the reaction and the characterization of its mechanism. The results obtained in this study suggest the existence of two patterns of interactions between loganic acid methyltransferase and the substrate. The role of residue Q38 in the binding and orientation of the substrate’s carboxyl group was also demonstrated. By employing a combined MD and QM approach, the experimental reaction barrier was reproduced, and detailed insights into the enzymatic activity mechanism of loganic acid methyltransferase were revealed. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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19 pages, 3134 KiB

Open AccessArticle

Detailed Experimental and In Silico Investigation of Indomethacin Binding with Human Serum Albumin Considering Primary and Secondary Binding Sites

by Mohd Sajid Ali, Jayaraman Muthukumaran, Monika Jain, Mohammad Tariq, Hamad A. Al-Lohedan and Abdullah Saad S. Al-Sanea

Molecules 2023, 28(7), 2979; https://doi.org/10.3390/molecules28072979 - 27 Mar 2023

Cited by 7 | Viewed by 2486

Abstract

The interaction of indomethacin with human serum albumin (HSA) has been studied here considering the primary and secondary binding sites. The Stern–Volmer plots were linear in the lower concentration range of indomethacin while a downward curvature was observed in the higher concentration range, [...] Read more.

The interaction of indomethacin with human serum albumin (HSA) has been studied here considering the primary and secondary binding sites. The Stern–Volmer plots were linear in the lower concentration range of indomethacin while a downward curvature was observed in the higher concentration range, suggesting the presence of more than one binding site for indomethacin inside HSA due to which the microenvironment of the fluorophore changed slightly and some of its fraction was not accessible to the quencher. The Stern–Volmer quenching constants (K_SV) for the primary and secondary sites were calculated from the two linear portions of the Stern–Volmer plots. There was around a two-fold decrease in the quenching constants for the low-affinity site as compared to the primary binding site. The interaction takes place via a static quenching mechanism and the K_SV decreases at both primary and secondary sites upon increasing the temperature. The binding constants were also evaluated, which show strong binding at the primary site and fair binding at the secondary site. The binding was thermodynamically favorable with the liberation of heat and the ordering of the system. In principle, hydrogen bonding and Van der Waals forces were involved in the binding at the primary site while the low-affinity site interacted through hydrophobic forces only. The competitive binding was also evaluated using warfarin, ibuprofen, hemin, and a warfarin + hemin combination as site markers. The binding profile remained unchanged in the presence of ibuprofen, whereas it decreased in the presence of both warfarin and hemin with a straight line in the Stern–Volmer plots. The reduction in the binding was at a maximum when both warfarin and hemin were present simultaneously with the downward curvature in the Stern–Volmer plots at higher concentrations of indomethacin. The secondary structure of HSA also changes slightly in the presence of higher concentrations of indomethacin. Molecular dynamics simulations were performed at the primary and secondary binding sites of HSA which are drug site 1 (located in the subdomain IIA of the protein) and the hemin binding site (located in subdomain IB), respectively. From the results obtained from molecular docking and MD simulation, the indomethacin molecule showed more binding affinity towards drug site 1 followed by the other two sites. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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20 pages, 3803 KiB

Open AccessArticle

Investigation of Newly Synthesized Bis-Acyl-Thiourea Derivatives of 4-Nitrobenzene-1,2-Diamine for Their DNA Binding, Urease Inhibition, and Anti-Brain-Tumor Activities

by Nasima Arshad, Uzma Parveen, Pervaiz Ali Channar, Aamer Saeed, Waseem Sharaf Saeed, Fouzia Perveen, Aneela Javed, Hammad Ismail, Muhammad Ismail Mir, Atteeque Ahmed, Basit Azad and Ishaq Khan

Molecules 2023, 28(6), 2707; https://doi.org/10.3390/molecules28062707 - 16 Mar 2023

Cited by 10 | Viewed by 3215

Abstract

Bis-acyl-thiourea derivatives, namely N,N’-(((4-nitro-1,2-phenylene)bis(azanediyl)) bis(carbonothioyl))bis(2,4-dichlorobenzamide) (UP-1), N,N’-(((4-nitro-1,2-phenylene) bis(azanediyl))bis(carbonothioyl))diheptanamide (UP-2), and N,N’-(((4-nitro-1,2-phenylene)bis(azanediyl))bis(carbonothioyl))dibutannamide (UP-3), were synthesized in two steps. The structural characterization of the derivatives was carried out by FTIR, ¹H-NMR, and ¹³C-NMR, and then their DNA binding, anti-urease, and [...] Read more.

Bis-acyl-thiourea derivatives, namely N,N’-(((4-nitro-1,2-phenylene)bis(azanediyl)) bis(carbonothioyl))bis(2,4-dichlorobenzamide) (UP-1), N,N’-(((4-nitro-1,2-phenylene) bis(azanediyl))bis(carbonothioyl))diheptanamide (UP-2), and N,N’-(((4-nitro-1,2-phenylene)bis(azanediyl))bis(carbonothioyl))dibutannamide (UP-3), were synthesized in two steps. The structural characterization of the derivatives was carried out by FTIR, ¹H-NMR, and ¹³C-NMR, and then their DNA binding, anti-urease, and anticancer activities were explored. Both theoretical and experimental results, as obtained by density functional theory, molecular docking, UV-visible spectroscopy, fluorescence (Flu-)spectroscopy, cyclic voltammetry (CV), and viscometry, pointed towards compounds’ interactions with DNA. However, the values of binding constant (K_b), binding site size (n), and negative Gibbs free energy change (ΔG) (as evaluated by docking, UV-vis, Flu-, and CV) indicated that all the derivatives exhibited binding interactions with the DNA in the order UP-3 > UP-2 > UP-1. The experimental findings from spectral and electrochemical analysis complemented each other and supported the theoretical analysis. The lower diffusion coefficient (D_o) values, as obtained from CV responses of each compound after DNA addition at various scan rates, further confirmed the formation of a bulky compound–DNA complex that caused slow diffusion. The mixed binding mode of interaction as seen in docking was further verified by changes in DNA viscosity with varying compound concentrations. All compounds showed strong anti-urease activity, whereas UP-1 was found to have comparatively better inhibitory efficiency, with an IC₅₀ value of 1.55 ± 0.0288 µM. The dose-dependent cytotoxicity of the synthesized derivatives against glioblastoma MG-U87 cells (a human brain cancer cell line) followed by HEK-293 cells (a normal human embryonic kidney cell line) indicated that UP-1 and UP-3 have greater cytotoxicity against both cancerous and healthy cell lines at 400 µM. However, dose-dependent responses of UP-2 showed cytotoxicity against cancerous cells, while it showed no cytotoxicity on the healthy cell line at a low concentration range of 40–120 µM. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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9 pages, 2259 KiB

Open AccessArticle

(-)-Epigallocatechin-3-gallate Directly Binds Cyclophilin D: A Potential Mechanism for Mitochondrial Protection

by Annan Wu, Jie Zhang, Quanhong Li, Xiaojun Liao, Chunyu Wang and Jing Zhao

Molecules 2022, 27(24), 8661; https://doi.org/10.3390/molecules27248661 - 7 Dec 2022

Cited by 1 | Viewed by 1503

Abstract

(1) Background: (-)-Epigallocatechin-3-gallate (EGCG) has been reported to improve mitochondrial function in cell models, while the underlying mechanism is not clear. Cyclophilin D (CypD) is a key protein that regulates mitochondrial permeability transition pore (mPTP) opening. (2) Methods: In this study, we found [...] Read more.

(1) Background: (-)-Epigallocatechin-3-gallate (EGCG) has been reported to improve mitochondrial function in cell models, while the underlying mechanism is not clear. Cyclophilin D (CypD) is a key protein that regulates mitochondrial permeability transition pore (mPTP) opening. (2) Methods: In this study, we found that EGCG directly binds to CypD and this interaction was investigated by surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) and molecular dynamic (MD) simulation. (3) Results: SPR showed an affinity of 2.7 × 10⁻⁵ M. The binding sites of EGCG on CypD were mapped to three regions by 2D NMR titration, which are Region 1 (E23-V29), Region 2 (T89-G104) and Region 3 (G124-I133). Molecular docking showed binding interface consistent with 2D NMR titration. MD simulations revealed that at least two conformations of EGCG-CypD complex exist, one with E23, D27, L90 and V93 as the most contributed residues and E23, L5 and I133 for the other. The major driven force for EGCG-CypD binding are Van der Waals and electrostatic interactions. (4) Conclusions: These results provide the structural basis for EGCG-CypD interaction, which might be a potential mechanism of how EGCG protects mitochondrial functions. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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17 pages, 6437 KiB

Open AccessArticle

Insight into the Interaction Mechanism of HSA with Aztreonam: A Multispectroscopic and Computational Approach

by Amal A. Sabour, Altaf Khan and Mohammed R. Alhuzani

Molecules 2022, 27(22), 7858; https://doi.org/10.3390/molecules27227858 - 14 Nov 2022

Cited by 8 | Viewed by 1741

Abstract

Aztreonam is a Gram-negative bacteria-targeting synthetic monobactam antibiotic. Human serum albumin (HSA) plays an important role in the transference of pharmaceuticals, hormones, and fatty acids, along with other compounds, determining their biodistribution and physiological fate. Using several biophysical and in silico approaches, we [...] Read more.

Aztreonam is a Gram-negative bacteria-targeting synthetic monobactam antibiotic. Human serum albumin (HSA) plays an important role in the transference of pharmaceuticals, hormones, and fatty acids, along with other compounds, determining their biodistribution and physiological fate. Using several biophysical and in silico approaches, we studied the interaction of aztreonam with HSA under physiological environments in this study. Results confirm the formation of HSA-aztreonam complex where aztreonam showed moderate affinity towards HSA. A static mode of quenching was confirmed from the steady state fluorescence data. FRET findings also showed that there was a significant feasibility of energy transfer between HSA and aztreonam. Site marker displacement experimental conclusion suggested the binding site of aztreonam was the sub-domain IB of HSA. Circular dichroic spectroscopic analysis suggested that aztreonam interaction decreases the α-helical content of HSA. Changes in microenvironment were studied through synchronous fluorescence data. According to molecular docking results, the HSA-aztreonam complex is mostly maintained by non-covalent forces, with a binding energy of 7.7 kcal mol⁻¹. The presence of a hydrogen bond, van der Waal interaction, and pi-anion interaction in the binding process, as well as conformational changes in HSA after binding with aztreonam, are all confirmed by molecular dynamic simulation. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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16 pages, 4129 KiB

Open AccessArticle

In-Silico Analysis of Phytocompounds of Olea europaea as Potential Anti-Cancer Agents to Target PKM2 Protein

by Faizan Abul Qais, Suliman Yousef Alomar, Mohammad Azhar Imran and Md Amiruddin Hashmi

Molecules 2022, 27(18), 5793; https://doi.org/10.3390/molecules27185793 - 7 Sep 2022

Cited by 15 | Viewed by 2500

Abstract

Globally, cancer is the second leading cause of mortality and morbidity. The growth and development of cancer are extremely complex. It is caused by a variety of pathways and involves various types of enzymes. Pyruvate kinase M2 (PKM2) is an isoform of pyruvate [...] Read more.

Globally, cancer is the second leading cause of mortality and morbidity. The growth and development of cancer are extremely complex. It is caused by a variety of pathways and involves various types of enzymes. Pyruvate kinase M2 (PKM2) is an isoform of pyruvate kinase, that catalyses the last steps of glycolysis to produce energy. PKM2 is relatively more expressed in tumour cells where it tends to exist in a dimer form. Various medicinal plants are available that contain a variety of micronutrients to combat against different cancers. The phytocompounds of the olive tree (Olea europaea) leaves play an important role in inhibiting the proliferation of several cancers. In this study, the phytocompounds of olive leaf extract (OLE) were studied using various in silico tools, such as pkCSM software to predict ADMET properties and PASS Online software to predict anticancer activity. However, the molecular docking study provided the binding energies and inhibition constant and confirmed the interaction between PKM2 and the ligands. The dynamic behaviour, conformational changes, and stability between PKM2 and the top three hit compounds (Verbascoside (Ver), Rutin (Rut), and Luteolin_7_O_glucoside (Lut)) are studied by MD simulations. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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18 pages, 4709 KiB

Open AccessArticle

PI3K/mTOR Dual Inhibitor Pictilisib Stably Binds to Site I of Human Serum Albumin as Observed by Computer Simulation, Multispectroscopic, and Microscopic Studies

by Hongqin Yang, Yanjun Ma, Hongjie Zhang and Junyi Ma

Molecules 2022, 27(16), 5071; https://doi.org/10.3390/molecules27165071 - 9 Aug 2022

Cited by 2 | Viewed by 1922

Abstract

Pictilisib (GDC-0941) is a well-known dual inhibitor of class I PI3K and mTOR and is presently undergoing phase 2 clinical trials for cancer treatment. The present work investigated the dynamic behaviors and interaction mechanism between GDC-0941 and human serum albumin (HSA). Molecular docking [...] Read more.

Pictilisib (GDC-0941) is a well-known dual inhibitor of class I PI3K and mTOR and is presently undergoing phase 2 clinical trials for cancer treatment. The present work investigated the dynamic behaviors and interaction mechanism between GDC-0941 and human serum albumin (HSA). Molecular docking and MD trajectory analyses revealed that GDC-0941 bound to HSA and that the binding site was positioned in subdomain IIA at Sudlow’s site I of HSA. The fluorescence intensity of HSA was strongly quenched by GDC-0941, and results showed that the HSA–GDC-0941 interaction was a static process caused by ground-state complex formation. The association constant of the HSA–GDC-0941 complex was approximately 10⁵ M⁻¹, reflecting moderate affinity. Thermodynamic analysis conclusions were identical with MD simulation results, which revealed that van der Waals interactions were the vital forces involved in the binding process. CD, synchronous, and 3D fluorescence spectroscopic results revealed that GDC-0941 induced the structural change in HSA. Moreover, the conformational change of HSA affected its molecular sizes, as evidenced by AFM. This work provides a useful research strategy for exploring the interaction of GDC-0941 with HSA, thus helping in the understanding of the transport and delivery of dual inhibitors in the blood circulation system. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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17 pages, 4284 KiB

Open AccessArticle

Chalcone Scaffolds Exhibiting Acetylcholinesterase Enzyme Inhibition: Mechanistic and Computational Investigations

by Yossra A. Malik, Talal Ahmed Awad, Mohnad Abdalla, Sakina Yagi, Hassan A. Alhazmi, Waquar Ahsan, Mohammed Albratty, Asim Najmi, Shabbir Muhammad and Asaad Khalid

Molecules 2022, 27(10), 3181; https://doi.org/10.3390/molecules27103181 - 16 May 2022

Cited by 6 | Viewed by 2571

Abstract

This study was aimed to perform the mechanistic investigations of chalcone scaffold as inhibitors of acetylcholinesterase (AChE) enzyme using molecular docking and molecular dynamics simulation tools. Basic chalcones (C1–C5) were synthesized and their in vitro AChE inhibition was tested. [...] Read more.

This study was aimed to perform the mechanistic investigations of chalcone scaffold as inhibitors of acetylcholinesterase (AChE) enzyme using molecular docking and molecular dynamics simulation tools. Basic chalcones (C1–C5) were synthesized and their in vitro AChE inhibition was tested. Binding interactions were studied using AutoDock and Surflex-Dock programs, whereas the molecular dynamics simulation studies were performed to check the stability of the ligand–protein complex. Good AChE inhibition (IC₅₀ = 22 ± 2.8 to 37.6 ± 0.75 μM) in correlation with the in silico results (binding energies = −8.55 to −8.14 Kcal/mol) were obtained. The mechanistic studies showed that all of the functionalities present in the chalcone scaffold were involved in binding with the amino acid residues at the binding site through hydrogen bonding, π–π, π–cation, π–sigma, and hydrophobic interactions. Molecular dynamics simulation studies showed the formation of stable complex between the AChE enzyme and C4 ligand. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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17 pages, 6818 KiB

Open AccessArticle

Antibacterial Mechanisms of Zinc Oxide Nanoparticle against Bacterial Food Pathogens Resistant to Beta-Lactam Antibiotics

by Rajapandiyan Krishnamoorthy, Jegan Athinarayanan, Vaiyapuri Subbarayan Periyasamy, Mohammad A. Alshuniaber, Ghedeir Alshammari, Mohammed Jamal Hakeem, Mohammed Asif Ahmed and Ali A. Alshatwi

Molecules 2022, 27(8), 2489; https://doi.org/10.3390/molecules27082489 - 12 Apr 2022

Cited by 56 | Viewed by 3615

Abstract

The increase in β-lactam-resistant Gram-negative bacteria is a severe recurrent problem in the food industry for both producers and consumers. The development of nanotechnology and nanomaterial applications has transformed many features in food science. The antibacterial activity of zinc oxide nanoparticles (ZnO NPs) [...] Read more.

The increase in β-lactam-resistant Gram-negative bacteria is a severe recurrent problem in the food industry for both producers and consumers. The development of nanotechnology and nanomaterial applications has transformed many features in food science. The antibacterial activity of zinc oxide nanoparticles (ZnO NPs) and their mechanism of action on β-lactam-resistant Gram-negative food pathogens, such as Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Serratia marcescens, Klebsiella pneumoniae, and Proteus mirabilis, are investigated in the present paper. The study results demonstrate that ZnO NPs possesses broad-spectrum action against these β-lactamase-producing strains. The minimal inhibitory and minimal bactericidal concentrations vary from 0.04 to 0.08 and 0.12 to 0.24 mg/mL, respectively. The ZnO NPs elevate the level of reactive oxygen species (ROS) and malondialdehyde in the bacterial cells as membrane lipid peroxidation. It has been confirmed from the transmission electron microscopy image of the treated bacterial cells that ZnO NPs diminish the permeable membrane, denature the intracellular proteins, cause DNA damage, and cause membrane leakage. Based on these findings, the action of ZnO NPs has been attributed to the fact that broad-spectrum antibacterial action against β-lactam-resistant Gram-negative food pathogens is mediated by Zn²⁺ ion-induced oxidative stress, actions via lipid peroxidation and membrane damage, subsequently resulting in depletion, leading to β-lactamase enzyme inhibition, intracellular protein inactivation, DNA damage, and eventually cell death. Based on the findings of the present study, ZnO NPs can be recommended as potent broad-spectrum antibacterial agents against β-lactam-resistant Gram-negative pathogenic strains. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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20 pages, 10919 KiB

Open AccessArticle

Experimental and Computational Investigation on the Interaction of Anticancer Drug Gemcitabine with Human Plasma Protein: Effect of Copresence of Ibuprofen on the Binding

by Mohd Sajid Ali and Hamad A. Al-Lohedan

Molecules 2022, 27(5), 1635; https://doi.org/10.3390/molecules27051635 - 1 Mar 2022

Cited by 11 | Viewed by 2895

Abstract

The interaction of common anticancer drug gemcitabine with human serum albumin (HSA) has been studied in detail. The effect of an omnipresent nonsteroidal anti-inflammatory drug ibuprofen was also seen on the binding of HSA and gemcitabine. A slight hyperchromic shift in the difference [...] Read more.

The interaction of common anticancer drug gemcitabine with human serum albumin (HSA) has been studied in detail. The effect of an omnipresent nonsteroidal anti-inflammatory drug ibuprofen was also seen on the binding of HSA and gemcitabine. A slight hyperchromic shift in the difference UV-visible absorption spectra of HSA on the addition of gemcitabine gave a primary idea of the possible complex formation between them. The inner filter effect, which happens due to the significant absorbance of the ligand at the excitation and/or emission wavelengths, played an important role in the observed fluorescence quenching of HSA by gemcitabine that can be understood by comparing the observed and corrected fluorescence intensities obtained at λ_ex = 280 nm and 295 nm. Gemcitabine showed weak interaction with HSA, which took place via a dynamic quenching mechanism with 1:1 cooperative binding between them. Secondary structural analysis, based on circular dichroism (CD) spectroscopy, showed that low concentrations of gemcitabine did not affect the native structure of protein; however, higher concentrations affected it slightly with partial unfolding. For understanding the binding site of gemcitabine within HSA, both experimental (using site markers, warfarin and ibuprofen) as well as computational methods were employed, which revealed that the gemcitabine binding site is located between the interface of subdomain IIA and IIB within the close proximity of the warfarin site (drug site 1). The effect of ibuprofen on the binding was further elaborated because of the possibility of its coexistence with gemcitabine in the prescription given to the cancer patients, and it was noticed that, ibuprofen, even present in high amounts, did not affect the binding efficacy of gemcitabine with HSA. DFT analyses of various conformers of gemcitabine obtained from its docking with various structures of HSA (free and bounded with site markers), show that the stability of the gemcitabine molecule increased slightly after binding with ibuprofen-complexed HSA. Both experimental as well as computational results were in good agreement with each other. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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15 pages, 20348 KiB

Open AccessArticle

Plasma Bead Entrapped Liposomes as a Potential Drug Delivery System to Combat Fungal Infections

by Munazza Tamkeen Fatima, Zeyaul Islam, Ejaj Ahmad, Mehboob Hoque and Marriam Yamin

Molecules 2022, 27(3), 1105; https://doi.org/10.3390/molecules27031105 - 7 Feb 2022

Cited by 1 | Viewed by 2426

Abstract

Fibrin-based systems offer promises in drug and gene delivery as well as tissue engineering. We established earlier a fibrin-based plasma beads (PB) system as an efficient carrier of drugs and antigens. In the present work, attempts were made to further improve its therapeutic [...] Read more.

Fibrin-based systems offer promises in drug and gene delivery as well as tissue engineering. We established earlier a fibrin-based plasma beads (PB) system as an efficient carrier of drugs and antigens. In the present work, attempts were made to further improve its therapeutic efficacy exploiting innovative ideas, including the use of plasma alginate composite matrices, proteolytic inhibitors, cross linkers, and dual entrapment in various liposomal formulations. In vitro efficacy of the different formulations was examined. Pharmacokinetics of the formulations encapsulating Amphotericin B (AmpB), an antifungal compound, were investigated in Swiss albino mice. While administration of the free AmpB led to its rapid elimination (<72 h), PB/liposome-PB systems were significantly effective in sustaining AmpB release in the circulation (>144 h) and its gradual accumulation in the vital organs, also compared to the liposomal formulations alone. Interestingly, the slow release of AmpB from PB was unusual compared to other small molecules in our earlier findings, suggesting strong interaction with plasma proteins. Molecular interaction studies of bovine serum albumin constituting approximately 60% of plasma with AmpB using isothermal titration calorimetry and in silico docking verify these interactions, explaining the slow release of AmpB entrapped in PB alone. The above findings suggest that PB/liposome-PB could be used as safe and effective delivery systems to combat fungal infections in humans. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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23 pages, 20653 KiB

Open AccessArticle

The Antiproliferative and Apoptotic Effects of a Novel Quinazoline Carrying Substituted-Sulfonamides: In Vitro and Molecular Docking Study

by Ali S. Alqahtani, Mostafa M. Ghorab, Fahd A. Nasr, Mohammad Z. Ahmed, Abdullah A. Al-Mishari and Sabry M. Attia

Molecules 2022, 27(3), 981; https://doi.org/10.3390/molecules27030981 - 1 Feb 2022

Cited by 9 | Viewed by 2093

Abstract

In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position 4a–n. The structure of the newly prepared compounds was proved by microanalysis, IR, [...] Read more.

In order to investigate for a new effective and safe anticancer drug, we synthesized a novel series of quinazoline containing biologically active substituted-sulfonamide moiety at 3- position 4a–n. The structure of the newly prepared compounds was proved by microanalysis, IR, ¹H-NMR, ¹³C-NMR and mass spectral data. All the synthesized compounds were evaluated for their in vitro cytotoxic activity in numerous cancer cell lines including A549, HepG-2, LoVo and MCF-7 and normal HUVEC cell line. The two most active compounds 4d and 4f were then tested for their apoptosis induction using DNA content and Annexin V-FITC/PI staining. Moreover, apoptosis initiation was also confirmed using RT-PCR and Western blot. To further understand the binding preferences of quinazoline sulfonamides, docking simulations were used. Among the fourteen new synthesized compounds, we found that compounds 4d and 4f exerted the strongest cytotoxicity against MCF-7 cells with an IC₅₀ value of 2.5 and 5 μM, respectively. Flow cytometry data revealed the ability of compounds 4d and 4f to mediate apoptosis and arrest cell cycle growth at G1 phase. Furthermore, RT-PCR and Western blot results suggested that both 4d and 4f activates apoptotic cell death pathway in MCF-7 cells. Molecular docking assessments indicated that compounds 4d and 4f fit perfectly into Bcl2’s active site. Based on the biological properties, we conclude that both compounds 4d and 4f could be used as a new type of anticancer agent, which provides a scientific basis for further research into the treatment of cancer. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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Review

Jump to: Research

18 pages, 6578 KiB

Open AccessReview

On Water Arrangements in Right- and Left-Handed DNA Structures

by Liliya A. Yatsunyk and Stephen Neidle

Molecules 2024, 29(2), 505; https://doi.org/10.3390/molecules29020505 - 19 Jan 2024

Cited by 1 | Viewed by 1683

Abstract

DNA requires hydration to maintain its structural integrity. Crystallographic analyses have enabled patterns of water arrangements to be visualized. We survey these water motifs in this review, focusing on left- and right-handed duplex and quadruplex DNAs, together with the i-motif. Common patterns of [...] Read more.

DNA requires hydration to maintain its structural integrity. Crystallographic analyses have enabled patterns of water arrangements to be visualized. We survey these water motifs in this review, focusing on left- and right-handed duplex and quadruplex DNAs, together with the i-motif. Common patterns of linear spines of water organization in grooves have been identified and are widely prevalent in right-handed duplexes and quadruplexes. By contrast, a left-handed quadruplex has a distinctive wheel of hydration populating the almost completely circular single groove in this structure. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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44 pages, 1685 KiB

Open AccessReview

Therapeutic Antibodies in Medicine

by Prerna Sharma, Rahul V. Joshi, Robert Pritchard, Kevin Xu and Maya A. Eicher

Molecules 2023, 28(18), 6438; https://doi.org/10.3390/molecules28186438 - 5 Sep 2023

Cited by 14 | Viewed by 6692

Abstract

Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on developing the first monoclonal antibody four decades ago has witnessed exponential growth in the last 10–15 years, where regulators have approved [...] Read more.

Antibody engineering has developed into a wide-reaching field, impacting a multitude of industries, most notably healthcare and diagnostics. The seminal work on developing the first monoclonal antibody four decades ago has witnessed exponential growth in the last 10–15 years, where regulators have approved monoclonal antibodies as therapeutics and for several diagnostic applications, including the remarkable attention it garnered during the pandemic. In recent years, antibodies have become the fastest-growing class of biological drugs approved for the treatment of a wide range of diseases, from cancer to autoimmune conditions. This review discusses the field of therapeutic antibodies as it stands today. It summarizes and outlines the clinical relevance and application of therapeutic antibodies in treating a landscape of diseases in different disciplines of medicine. It discusses the nomenclature, various approaches to antibody therapies, and the evolution of antibody therapeutics. It also discusses the risk profile and adverse immune reactions associated with the antibodies and sheds light on future applications and perspectives in antibody drug discovery. Full article

(This article belongs to the Special Issue Biomolecules Interactions with Small Molecules)

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