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Molecular Modeling Analysis and Conformational Search of Natural Products and Synthesized Compounds

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

Deadline for manuscript submissions: closed (30 October 2020) | Viewed by 15680

Special Issue Editor

Prof. Dr. Anna Artese

E-Mail Website
Guest Editor
Dipartimento di Scienze della Salute, Università “Magna Graecia” di Catanzaro, Campus “Salvatore Venuta”, Viale Europa, 88100 Catanzaro, Italy
Interests: drug design; molecular modeling; molecular dynamics; virtual screening; pharmacophore modeling; drug repurposing; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last two decades, molecular modeling has played a pivotal role in the rational drug discovery process due to improved computational technologies and the availability of structural and biological information on active compounds and potential targets. In order to design a potent and selective drug, it is crucial to understand essential ligand–receptor interactions by analyzing structural information from X-ray crystal and NMR structures of ligand–protein complexes. Ligand conformational properties are of key importance both in structure-based and in ligand-based design. Accounting for the full molecular flexibility of both ligands and proteins simultaneously is extremely complex, and the need for low-energy conformers, especially aimed at finding bioactive conformation, has been long recognized. Therefore, several search algorithms and sampling methods have been developed and implemented in protocols for generating conformers of small, drug-like molecules. In this context, the study of natural products is still attracting a great scientific attention, and their current importance as valuable leads for drug discovery is undebatable.

The aim of this Special Issue is to present a modern overview of recent developments in molecular modeling analysis and the conformational search for natural products and synthesized compounds. Reviews, full papers, and short communications, covering the methodological and theoretical aspects of the current trends in the drug discovery process, are all welcome.

Dr. Anna Artese
Guest Editor

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Keywords

  • Conformational search
  • Preorganization
  • Molecular docking
  • Protein–ligand interactions
  • Molecular interaction fields
  • Molecular dynamics
  • Pharmacophore modeling
  • Structure-based and ligand-based virtual screening
  • Natural compounds
  • Synthetic compounds
  • Enhanced sampling methods.

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Related Special Issue

Published Papers (5 papers)

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Research

15 pages, 2866 KiB  
Article
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 2570
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  
Article
Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B 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 8 | Viewed by 3736
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-HT2B 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  
Article
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
Cited by 1 | Viewed by 2456
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  
Article
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 12 | Viewed by 3337
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  
Article
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 4 | Viewed by 2743
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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