Research

17 pages, 4705 KiB

Open AccessArticle

Pharmacophore-Oriented Identification of Potential Leads as CCR5 Inhibitors to Block HIV Cellular Entry

by Pooja Singh, Vikas Kumar, Gihwan Lee, Tae Sung Jung, Min Woo Ha, Jong Chan Hong and Keun Woo Lee

Int. J. Mol. Sci. 2022, 23(24), 16122; https://doi.org/10.3390/ijms232416122 - 17 Dec 2022

Viewed by 1992

Abstract

Cysteine–cysteine chemokine receptor 5 (CCR5) has been discovered as a co-receptor for cellular entry of human immunodeficiency virus (HIV). Moreover, the role of CCR5 in a variety of cancers and various inflammatory responses was also discovered. Despite the fact that several CCR5 antagonists [...] Read more.

Cysteine–cysteine chemokine receptor 5 (CCR5) has been discovered as a co-receptor for cellular entry of human immunodeficiency virus (HIV). Moreover, the role of CCR5 in a variety of cancers and various inflammatory responses was also discovered. Despite the fact that several CCR5 antagonists have been investigated in clinical trials, only Maraviroc has been licensed for use in the treatment of HIV patients. This indicates that there is a need for novel CCR5 antagonists. Keeping this in mind, the present study was designed. The active CCR5 inhibitors with known IC₅₀ value were selected from the literature and utilized to develop a ligand-based common feature pharmacophore model. The validated pharmacophore model was further used for virtual screening of drug-like databases obtained from the Asinex, Specs, InterBioScreen, and Eximed chemical libraries. Utilizing computational methods such as molecular docking studies, molecular dynamics simulations, and binding free energy calculation, the binding mechanism of selected inhibitors was established. The identified Hits not only showed better binding energy when compared to Maraviroc, but also formed stable interactions with the key residues and showed stable behavior throughout the 100 ns MD simulation. Our findings suggest that Hit1 and Hit2 may be potential candidates for CCR5 inhibition, and, therefore, can be considered for further CCR5 inhibition programs. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Research of Natural Products and Synthesized Compounds)

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16 pages, 1825 KiB

Open AccessArticle

Molecular Basis for Non-Covalent, Non-Competitive FAAH Inhibition

by Carmine Marco Morgillo, Antonio Lupia, Alessandro Deplano, Luciano Pirone, Bianca Fiorillo, Emilia Pedone, F. Javier Luque, Valentina Onnis, Federica Moraca and Bruno Catalanotti

Int. J. Mol. Sci. 2022, 23(24), 15502; https://doi.org/10.3390/ijms232415502 - 07 Dec 2022

Cited by 2 | Viewed by 1375

Abstract

Fatty acid amide hydrolase (FAAH) plays a key role in the control of cannabinoid signaling and it represents a promising therapeutic strategy for the treatment of a wide range of diseases, including neuropathic pain and chronic inflammation. Starting from kinetics experiments carried out [...] Read more.

Fatty acid amide hydrolase (FAAH) plays a key role in the control of cannabinoid signaling and it represents a promising therapeutic strategy for the treatment of a wide range of diseases, including neuropathic pain and chronic inflammation. Starting from kinetics experiments carried out in our previous work for the most potent inhibitor 2-amino-3-chloropyridine amide (TPA14), we have investigated its non-competitive mechanism of action using molecular dynamics, thermodynamic integration and QM-MM/GBSA calculations. The computational studies highlighted the impact of mutations on the receptor binding pockets and elucidated the molecular basis of the non-competitive inhibition mechanism of TPA14, which prevents the endocannabinoid anandamide (AEA) from reaching its pro-active conformation. Our study provides a rationale for the design of non-competitive potent FAAH inhibitors for the treatment of neuropathic pain and chronic inflammation. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Research of Natural Products and Synthesized Compounds)

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15 pages, 3879 KiB

Open AccessArticle

Computational Repurposing of Mitoxantrone-Related Structures against Monkeypox Virus: A Molecular Docking and 3D Pharmacophore Study

by Gagan Preet, Emmanuel T. Oluwabusola, Bruce Forbes Milne, Rainer Ebel and Marcel Jaspars

Int. J. Mol. Sci. 2022, 23(22), 14287; https://doi.org/10.3390/ijms232214287 - 18 Nov 2022

Cited by 11 | Viewed by 2325

Abstract

Monkeypox is caused by a DNA virus known as the monkeypox virus (MPXV) belonging to the Orthopoxvirus genus of the Poxviridae family. Monkeypox is a zoonotic disease where the primary significant hosts are rodents and non-human primates. There is an increasing global incidence [...] Read more.

Monkeypox is caused by a DNA virus known as the monkeypox virus (MPXV) belonging to the Orthopoxvirus genus of the Poxviridae family. Monkeypox is a zoonotic disease where the primary significant hosts are rodents and non-human primates. There is an increasing global incidence with a 2022 outbreak that has spread to Europe in the middle of the COVID-19 pandemic. The new outbreak has novel, previously undiscovered mutations and variants. Currently, the US Food and Drug Administration (FDA) approved poxvirus treatment involving the use of tecovirimat. However, there has otherwise been limited research interest in monkeypox. Mitoxantrone (MXN), an anthracycline derivative, an FDA-approved therapeutic for treating cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against the vaccinia virus and monkeypox virus. In this study, virtual screening, molecular docking analysis, and pharmacophore ligand-based modelling were employed on anthracene structures (1-13) closely related to MXN to explore the potential repurposing of multiple compounds from the PubChem library. Four chemical structures (2), (7), (10) and (12) show a predicted high binding potential to suppress viral replication. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Research of Natural Products and Synthesized Compounds)

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17 pages, 4740 KiB

Open AccessArticle

Allosteric Inhibition of Neutral Sphingomyelinase 2 (nSMase2) by DPTIP: From Antiflaviviral Activity to Deciphering Its Binding Site through In Silico Studies and Experimental Validation

by Hadrián Álvarez-Fernández, Patricia Mingo-Casas, Ana-Belén Blázquez, Flavia Caridi, Juan Carlos Saiz, María-Jesús Pérez-Pérez, Miguel A. Martín-Acebes and Eva-María Priego

Int. J. Mol. Sci. 2022, 23(22), 13935; https://doi.org/10.3390/ijms232213935 - 11 Nov 2022

Cited by 1 | Viewed by 1501

Abstract

Flavivirus comprises globally emerging and re-emerging pathogens such as Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV), among others. Although some vaccines are available, there is an unmet medical need as no effective antiviral treatment has been approved for flaviviral [...] Read more.

Flavivirus comprises globally emerging and re-emerging pathogens such as Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV), among others. Although some vaccines are available, there is an unmet medical need as no effective antiviral treatment has been approved for flaviviral infections. The development of host-directed antivirals (HDAs) targeting host factors that are essential for viral replication cycle offers the opportunity for the development of broad-spectrum antivirals. In the case of flaviviruses, recent studies have revealed that neutral sphingomyelinase 2, (nSMase2), involved in lipid metabolism, plays a key role in WNV and ZIKV infection. As a proof of concept, we have determined the antiviral activity of the non-competitive nSMase2 inhibitor DPTIP against WNV and ZIKV virus. DPTIP showed potent antiviral activity with EC₅₀ values of 0.26 µM and 1.56 µM for WNV and ZIKV, respectively. In order to unravel the allosteric binding site of DPTIP in nSMase2 and the details of the interaction, computational studies have been carried out. These studies have revealed that DPTIP could block the DK switch in nSMase2. Moreover, the analysis of the residues contributing to the binding identified His463 as a crucial residue. Interestingly, the inhibitory activity of DPTIP on the H463A mutant protein supported our hypothesis. Thus, an allosteric cavity in nSMase2 has been identified that can be exploited for the development of new inhibitors with anti-flaviviral activity. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Research of Natural Products and Synthesized Compounds)

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25 pages, 12504 KiB

Open AccessArticle

A Multistage In Silico Study of Natural Potential Inhibitors Targeting SARS-CoV-2 Main Protease

by Eslam B. Elkaeed, Ibrahim H. Eissa, Hazem Elkady, Ahmed Abdelalim, Ahmad M. Alqaisi, Aisha A. Alsfouk, Alaa Elwan and Ahmed M. Metwaly

Int. J. Mol. Sci. 2022, 23(15), 8407; https://doi.org/10.3390/ijms23158407 - 29 Jul 2022

Cited by 36 | Viewed by 2381

Abstract

Among a group of 310 natural antiviral natural metabolites, our team identified three compounds as the most potent natural inhibitors against the SARS-CoV-2 main protease (PDB ID: 5R84), M^pro. The identified compounds are sattazolin and caprolactin A and B. A validated [...] Read more.

Among a group of 310 natural antiviral natural metabolites, our team identified three compounds as the most potent natural inhibitors against the SARS-CoV-2 main protease (PDB ID: 5R84), M^pro. The identified compounds are sattazolin and caprolactin A and B. A validated multistage in silico study was conducted using several techniques. First, the molecular structures of the selected metabolites were compared with that of GWS, the co-crystallized ligand of M^pro, in a structural similarity study. The aim of this study was to determine the thirty most similar metabolites (10%) that may bind to the M^pro similar to GWS. Then, molecular docking against M^pro and pharmacophore studies led to the choice of five metabolites that exhibited good binding modes against the M^pro and good fit values against the generated pharmacophore model. Among them, three metabolites were chosen according to ADMET studies. The most promising M^pro inhibitor was determined by toxicity and DFT studies to be caprolactin A (292). Finally, molecular dynamics (MD) simulation studies were performed for caprolactin A to confirm the obtained results and understand the thermodynamic characteristics of the binding. It is hoped that the accomplished results could represent a positive step in the battle against COVID-19 through further in vitro and in vivo studies on the selected compounds. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Research of Natural Products and Synthesized Compounds)

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22 pages, 7635 KiB

Open AccessArticle

Multi-Step In Silico Discovery of Natural Drugs against COVID-19 Targeting Main Protease

by Eslam B. Elkaeed, Fadia S. Youssef, Ibrahim H. Eissa, Hazem Elkady, Aisha A. Alsfouk, Mohamed L. Ashour, Mahmoud A. El Hassab, Sahar M. Abou-Seri and Ahmed M. Metwaly

Int. J. Mol. Sci. 2022, 23(13), 6912; https://doi.org/10.3390/ijms23136912 - 21 Jun 2022

Cited by 43 | Viewed by 2618

Abstract

In continuation of our antecedent work against COVID-19, three natural compounds, namely, Luteoside C (130), Kahalalide E (184), and Streptovaricin B (278) were determined as the most promising SARS-CoV-2 main protease (M^pro) inhibitors among 310 [...] Read more.

In continuation of our antecedent work against COVID-19, three natural compounds, namely, Luteoside C (130), Kahalalide E (184), and Streptovaricin B (278) were determined as the most promising SARS-CoV-2 main protease (M^pro) inhibitors among 310 naturally originated antiviral compounds. This was performed via a multi-step in silico method. At first, a molecular structure similarity study was done with PRD_002214, the co-crystallized ligand of M^pro (PDB ID: 6LU7), and favored thirty compounds. Subsequently, the fingerprint study performed with respect to PRD_002214 resulted in the election of sixteen compounds (7, 128, 130, 156, 157, 158, 180, 184, 203, 204, 210, 237, 264, 276, 277, and 278). Then, results of molecular docking versus M^pro PDB ID: 6LU7 favored eight compounds (128, 130, 156, 180, 184, 203, 204, and 278) based on their binding affinities. Then, in silico toxicity studies were performed for the promising compounds and revealed that all of them have good toxicity profiles. Finally, molecular dynamic (MD) simulation experiments were carried out for compounds 130, 184, and 278, which exhibited the best binding modes against M^pro. MD tests revealed that luteoside C (130) has the greatest potential to inhibit SARS-CoV-2 main protease. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Research of Natural Products and Synthesized Compounds)

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16 pages, 2425 KiB

Open AccessArticle

Identification of Novel Natural Product Inhibitors against Matrix Metalloproteinase 9 Using Quantum Mechanical Fragment Molecular Orbital-Based Virtual Screening Methods

by Hocheol Lim, Hansol Hong, Seonik Hwang, Song Ja Kim, Sung Yum Seo and Kyoung Tai No

Int. J. Mol. Sci. 2022, 23(8), 4438; https://doi.org/10.3390/ijms23084438 - 18 Apr 2022

Cited by 6 | Viewed by 2136

Abstract

Matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases involved in multiple cellular processes. Among the MMP isoforms, MMP-9 regulates cancer invasion, rheumatoid arthritis, and osteoarthritis by degrading extracellular matrix proteins present in the tumor microenvironment and cartilage and promoting angiogenesis. Here, we identified two [...] Read more.

Matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases involved in multiple cellular processes. Among the MMP isoforms, MMP-9 regulates cancer invasion, rheumatoid arthritis, and osteoarthritis by degrading extracellular matrix proteins present in the tumor microenvironment and cartilage and promoting angiogenesis. Here, we identified two potent natural product inhibitors of the non-catalytic hemopexin domain of MMP-9 using a novel quantum mechanical fragment molecular orbital (FMO)-based virtual screening workflow. The workflow integrates qualitative pharmacophore modeling, quantitative binding affinity prediction, and a raw material search of natural product inhibitors with the BMDMS-NP library. In binding affinity prediction, we made a scoring function with the FMO method and applied the function to two protein targets (acetylcholinesterase and fibroblast growth factor 1 receptor) from DUD-E benchmark sets. In the two targets, the FMO method outperformed the Glide docking score and MM/PBSA methods. By applying this workflow to MMP-9, we proposed two potent natural product inhibitors (laetanine 9 and genkwanin 10) that interact with hotspot residues of the hemopexin domain of MMP-9. Laetanine 9 and genkwanin 10 bind to MMP-9 with a dissociation constant (K_D) of 21.6 and 0.614 μM, respectively. Overall, we present laetanine 9 and genkwanin 10 for MMP-9 and demonstrate that the novel FMO-based workflow with a quantum mechanical approach is promising to discover potent natural product inhibitors of MMP-9, satisfying the pharmacophore model and good binding affinity. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Research of Natural Products and Synthesized Compounds)

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12 pages, 2978 KiB

Open AccessArticle

Synthesis and Vibrational Circular Dichroism Analysis of N-Heterocyclic Carbene Precursors Containing Remote Chirality Centers

by Zita Szabó, Attila Paczal, Tibor Kovács, Attila Mándi, Andras Kotschy and Tibor Kurtán

Int. J. Mol. Sci. 2022, 23(7), 3471; https://doi.org/10.3390/ijms23073471 - 23 Mar 2022

Cited by 4 | Viewed by 1484

Abstract

VCD analysis of 16 diastereomeric pairs of NHC precursors containing two isolated chirality centers and different substitution patterns identified VCD transitions characteristic of the chirality center in the imidazolium ring or in the side chain, which, in contrast to ECD and OR, could [...] Read more.

VCD analysis of 16 diastereomeric pairs of NHC precursors containing two isolated chirality centers and different substitution patterns identified VCD transitions characteristic of the chirality center in the imidazolium ring or in the side chain, which, in contrast to ECD and OR, could be utilized to assign the two chirality centers separately by simple comparison, regardless of the type and position of achiral aromatic substituents. While the ECD and OR data showed great dependence on the position of an achiral substituent such as a methoxy group, characteristic experimental VCD transitions remained consistent and they could be used to determine the absolute configuration of all the regio- and stereoisomers and substituted analogues. VCD, ECD and OR approaches were evaluated, and several carbene precursors were found, for which only the VCD method could distinguish the four stereoisomers. With t-butyl, phenyl or 2-naphthyl substituents at the C-1′ chirality center, the ECD spectra of the C-1′ epimers were near-identical, and hence it was only the VCD approach that showed distinct differences suitable for the configurational assignment. The chiroptical characterization of our diastereomeric pairs of NHC precursors enables the future application of related derivatives having different substitution patterns in stereoselective transformations. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Research of Natural Products and Synthesized Compounds)

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15 pages, 2866 KiB

Open AccessArticle

Insights into Interactions between Interleukin-6 and Dendritic Polyglycerols

by Željka Sanader Maršić, Dušica Maysinger and Vlasta Bonačić-Kouteckỳ

Int. J. Mol. Sci. 2021, 22(5), 2415; https://doi.org/10.3390/ijms22052415 - 28 Feb 2021

Cited by 6 | Viewed by 2140

Abstract

Interleukin-6 (IL-6) is involved in physiological and pathological processes. Different pharmacological agents have been developed to block IL-6 deleterious effects and to recover homeostatic IL-6 signaling. One of the proposed nanostructures in pre-clinical investigations which reduced IL-6 concentrations is polyglycerol dendrimer, a nano-structure [...] Read more.

Interleukin-6 (IL-6) is involved in physiological and pathological processes. Different pharmacological agents have been developed to block IL-6 deleterious effects and to recover homeostatic IL-6 signaling. One of the proposed nanostructures in pre-clinical investigations which reduced IL-6 concentrations is polyglycerol dendrimer, a nano-structure with multiple sulfate groups. The aim of the present study was to uncover the type of binding between critical positions in the human IL-6 structure available for binding dPGS and compare it with heparin sulfate binding. We studied these interactions by performing docking simulations of dPGS and heparins with human IL-6 using AutoDock Vina. These molecular docking analyses indicate that the two ligands have comparable affinities for the positively charged positions on the surface of IL-6. All-atom molecular dynamics simulations (MD) employing Gromacs were used to explore the binding sites and binding strengths. Results suggest two major binding sites and show that the strengths of binding are similar for heparin and dPGS (−5.5–6.4 kcal/ mol). dPGS or its analogs could be used in the therapeutic intervention in sepsis and inflammatory disorders to reduce unbound IL-6 in the plasma or tissues and its binding to the receptors. We propose that analogs of dPGS could specifically block IL-6 binding in the desired signaling mode and would be valuable new probes to establish optimized therapeutic intervention in inflammation. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Search of Natural Products and Synthesized Compounds)

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14 pages, 2766 KiB

Open AccessArticle

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT_2B Receptors

by Katrin Denzinger, Trung Ngoc Nguyen, Theresa Noonan, Gerhard Wolber and Marcel Bermudez

Int. J. Mol. Sci. 2020, 21(24), 9728; https://doi.org/10.3390/ijms21249728 - 20 Dec 2020

Cited by 7 | Viewed by 3273

Abstract

G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible [...] Read more.

G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known β-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT_2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Search of Natural Products and Synthesized Compounds)

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16 pages, 2556 KiB

Open AccessArticle

In Silico Food-Drug Interaction: A Case Study of Eluxadoline and Fatty Meal

by Annalisa Maruca, Antonio Lupia, Roberta Rocca, Daniel Keszthelyi, Maura Corsetti and Stefano Alcaro

Int. J. Mol. Sci. 2020, 21(23), 9127; https://doi.org/10.3390/ijms21239127 - 30 Nov 2020

Viewed by 2043

Abstract

Food-drug interaction is an infrequently considered aspect in clinical practice. Usually, drugs are taken together with meals and what follows may adversely affect pharmacokinetic and pharmacodynamic properties, and hence, the therapeutic effects. In this study, a computational protocol was proposed to explain the [...] Read more.

Food-drug interaction is an infrequently considered aspect in clinical practice. Usually, drugs are taken together with meals and what follows may adversely affect pharmacokinetic and pharmacodynamic properties, and hence, the therapeutic effects. In this study, a computational protocol was proposed to explain the different assimilations of two µ-receptors agonists, eluxadoline and loperamide, with a peculiar pharmacokinetic profile. Compared to loperamide, eluxadoline is absorbed less after the intake of a fatty meal, and the LogP values do not explain this event. Firstly, keeping in mind the different pH in the intestinal tract, the protonation states of both compounds were calculated. Then, all structures were subjected to a conformational search by using MonteCarlo and Molecular Dynamics methods, with solvation terms mimicking the water and weak polar solvent (octanol). Both computational results showed that eluxadoline has less conformational freedom in octanol, unlike loperamide, which exhibits constant behavior in both solvents. Therefore, we hypothesize that fatty meal causes the “closure” of the eluxadoline molecule to prevent the exposure of the polar groups and their interaction with water, necessary for the drug absorption. Based on our results, this work could be a reasonable “case study”, useful for future investigation of the drug pharmacokinetic profile. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Search of Natural Products and Synthesized Compounds)

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19 pages, 5383 KiB

Open AccessArticle

Genes Identification, Molecular Docking and Dynamics Simulation Analysis of Laccases from Amylostereum areolatum Provides Molecular Basis of Laccase Bound to Lignin

by Ningning Fu, Jiaxing Li, Ming Wang, Lili Ren and Youqing Luo

Int. J. Mol. Sci. 2020, 21(22), 8845; https://doi.org/10.3390/ijms21228845 - 22 Nov 2020

Cited by 11 | Viewed by 2821

Abstract

An obligate mutualistic relationship exists between the fungus Amylostereum areolatum and woodwasp Sirex noctilio. The fungus digests lignin in the host pine, providing essential nutrients for the growing woodwasp larvae. However, the functional properties of this symbiosis are poorly described. In this [...] Read more.

An obligate mutualistic relationship exists between the fungus Amylostereum areolatum and woodwasp Sirex noctilio. The fungus digests lignin in the host pine, providing essential nutrients for the growing woodwasp larvae. However, the functional properties of this symbiosis are poorly described. In this study, we identified, cloned, and characterized 14 laccase genes from A. areolatum. These genes encoded proteins of 508 to 529 amino acids and contained three typical copper-oxidase domains, necessary to confer laccase activity. Besides, we performed molecular docking and dynamics simulation of the laccase proteins in complex with lignin compounds (monomers, dimers, trimers, and tetramers). AaLac2, AaLac3, AaLac6, AaLac8, and AaLac10 were found that had low binding energies with all lignin model compounds tested and three of them could maintain stability when binding to these compounds. Among these complexes, amino acid residues ALA, GLN, LEU, PHE, PRO, and SER were commonly present. Our study reveals the molecular basis of A. areolatum laccases interacting with lignin, which is essential for understanding how the fungus provides nutrients to S. noctilio. These findings might also provide guidance for the control of S. noctilio by informing the design of enzyme mutants that could reduce the efficiency of lignin degradation. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Search of Natural Products and Synthesized Compounds)

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15 pages, 4172 KiB

Open AccessArticle

Discovery of Tricyclic Pyranochromenone as Novel Bruton’s Tyrosine Kinase Inhibitors with In Vivo Antirheumatic Activity

by Hyewon Cho, Eun Lee, Hye Ah Kwon, Lee Seul, Hui-Jeon Jeon, Ji Hoon Yu, Jae-Ha Ryu and Raok Jeon

Int. J. Mol. Sci. 2020, 21(21), 7919; https://doi.org/10.3390/ijms21217919 - 25 Oct 2020

Cited by 3 | Viewed by 2282

Abstract

Bruton’s tyrosine kinase (BTK) is an attractive target for treating patients with B cell malignancies and autoimmune diseases. Many BTK inhibitors have been identified; however, like other kinase inhibitors, they lack diversity in their core structures. Therefore, it is important to secure a [...] Read more.

Bruton’s tyrosine kinase (BTK) is an attractive target for treating patients with B cell malignancies and autoimmune diseases. Many BTK inhibitors have been identified; however, like other kinase inhibitors, they lack diversity in their core structures. Therefore, it is important to secure a novel scaffold that occupies the adenine-binding site of BTK. We screened an in-house library of natural products and their analogs via a biochemical assay to identify a novel scaffold for targeting BTK. A pyranochromenone scaffold, derived from a natural active component decursin, was found to be effective at targeting BTK and was selected for further optimization. A series of pyranochromenone analogs was synthesized through the modification of pyranochromenone at the C7 position. Pyranochromenone compounds with an electrophilic warhead exhibited promising BTK inhibitory activity, with IC₅₀ values in the range of 0.5–0.9 µM. A docking study of the representative compound 8 provided a reasonable explanation for compound activity. Compound 8 demonstrated good selectivity over other associated kinases and decreased the production of proinflammatory cytokines in THP cells. Moreover, compound 8 presented significant in vivo efficacy in a murine model of collagen-induced arthritis. Full article

(This article belongs to the Special Issue Molecular Modeling Analysis and Conformational Search of Natural Products and Synthesized Compounds)

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