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Molecular Modeling: Advancements and Applications
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Molecular Modeling: Advancements and Applications

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Computational and Theoretical Chemistry".

Deadline for manuscript submissions: closed (15 April 2022) | Viewed by 43090

Special Issue Editor

Prof. Dr. Teobald Kupka

E-Mail Website
Guest Editor
Institute of Chemistry, University of Opole, 48, Oleska Street, 45-052 Opole, Poland
Interests: nuclear magnetic shielding tensor; GIAO NMR; indirect spin-spin coupling constants; ZPV corrections to nuclear magnetic shielding; temperature correction (TC); solvent effect; relativistic corrections (RC); bioactive compounds; natural products
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is generally accepted that quantum mechanics, theoretical chemistry, and theoretical  physics are all very hermetic branches of science. However, their more recent incarnations, such as computational chemistry and molecular modeling, are also widely used in the laboratory by more practically oriented scientists. This is mainly due to the enormous progress we have witnessed since the middle of the 20th century, in theoretical developments and even more in computer hardware and software. The first milestone in computational chemistry and molecular modeling developments can be traced back to the theoretical prediction of the hydrogen molecule dissociation energy by Włodzimierz Kołos and Lutosław Wolniewicz in 1960, surpassing the most accurate experimental values determined earlier by Gerhard Herzberg and his team. Later on, in 1998 John Pople was awarded the Nobel prize for his development of computational methods in quantum chemistry together with Walter Kohn, one of the fathers of the density functional theory. In the few most recent decades, both in basic and applied sciences, we have witnessed an avalanche of new methods and applications of molecular modeling in chemistry, pharmacy, and material sciences.

Molecular modeling has been used mainly for the following two reasons:

  1. Structure and property prediction of new molecular systems.
  2. Support for the analysis of experimental data, including UV–VIS, IR/Raman, and NMR spectra.

Presently, the quest for novel methodologies is challenged by drug design and material sciences.

One of the important factors in this race is software development. Among the important factors of molecular modeling developments is the demand for accuracy, achieved mainly for small molecular systems. With the increasing size and complexity of the systems under investigation, they are often treated at a lower level of theoretical sophistication. In both cases, the speed of computer calculation and the available storage size are the limiting factors.

The aim of this Special Issue is to provide potential readers with an overview of recent challenges and developments in the fields of computational chemistry and molecular modeling, particularly those pertaining to various spectroscopic methods employed by experimental chemists and scientists working in pharmacy and the material sciences.

Reviews, full papers, and short communications covering both the methodology and theory as well as the application aspects of molecular modeling are equally welcomed. The submission of papers addressing the topics listed below are particularly encouraged.

Dr. Teobald Kupka
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Quantum mechanics
  • Molecular mechanics (MM)
  • Molecular dynamics (MD)
  • Semi-empirical calculations
  • Ab initio methods
  • Post-Hartree–Fock methods
  • Density functional theory (DFT)
  • Software development
  • Achieving chemical accuracy
  • Thermochemistry and reactivity
  • Interaction energy
  • Covalent bonding and non-covalent interactions
  • Large molecular systems
  • IR, Raman, and NMR
  • Drug design
  • Nanomaterials and nanotechnology
  • Material sciences

Published Papers (16 papers)

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Research

12 pages, 3545 KiB  
Article
Density Functional Theory-Based Studies Predict Carbon Nanotubes as Effective Mycolactone Inhibitors
by Nafiu Suleiman, Abu Yaya, Michael D. Wilson, Solomon Aryee and Samuel K. Kwofie
Molecules 2022, 27(14), 4440; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27144440 - 11 Jul 2022
Cited by 3 | Viewed by 1530
Abstract
Fullerenes, boron nitride nanotubes (BNNTs), and carbon nanotubes (CNTs) have all been extensively explored for biomedical purposes. This work describes the use of BNNTs and CNTs as mycolactone inhibitors. Density functional theory (DFT) has been used to investigate the chemical properties and interaction [...] Read more.
Fullerenes, boron nitride nanotubes (BNNTs), and carbon nanotubes (CNTs) have all been extensively explored for biomedical purposes. This work describes the use of BNNTs and CNTs as mycolactone inhibitors. Density functional theory (DFT) has been used to investigate the chemical properties and interaction mechanisms of mycolactone with armchair BNNTs (5,5) and armchair CNTs (5,5). By examining the optimized structure and interaction energy, the intermolecular interactions between mycolactone and nanotubes were investigated. The findings indicate that mycolactone can be physically adsorbed on armchair CNTs in a stable condition, implying that armchair CNTs can be potential inhibitors of mycolactone. According to DOS plots and HOMO–LUMO orbital studies, the electronic characteristics of pure CNTs are not modified following mycolactone adsorption on the nanotubes. Because of mycolactone’s large π-π interactions with CNTs, the estimated interaction energies indicate that mycolactone adsorption on CNTs is preferable to that on BNNTs. CNTs can be explored as potentially excellent inhibitors of mycolactone toxins in biological systems. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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7 pages, 2034 KiB  
Article
The Glu143 Residue Might Play a Significant Role in T20 Peptide Binding to HIV-1 Receptor gp41: An In Silico Study
by Ahmed L. Alaofi
Molecules 2022, 27(12), 3936; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27123936 - 20 Jun 2022
Cited by 3 | Viewed by 1292
Abstract
Despite the enormous efforts made to develop other fusion inhibitors for HIV, the enfuvirtide (known as T20) peptide is the only approved HIV-1 inhibitory drug so far. Investigating the role of potential residues of the T20 peptide’s conformational dynamics could help us to [...] Read more.
Despite the enormous efforts made to develop other fusion inhibitors for HIV, the enfuvirtide (known as T20) peptide is the only approved HIV-1 inhibitory drug so far. Investigating the role of potential residues of the T20 peptide’s conformational dynamics could help us to understand the role of potential residues of the T20 peptide. We investigated T20 peptide conformation and binding interactions with the HIV-1 receptor (i.e., gp41) using MD simulations and docking techniques, respectively. Although the mutation of E143 into alanine decreased the flexibility of the E143A mutant, the conformational compactness of the mutant was increased. This suggests a potential role of E143 in the T20 peptide’s conformation. Interestingly, the free energy landscape showed a significant change in the wild-type T20 minimum, as the E143A mutant produced two observed minima. Finally, the docking results of T20 to the gp41 receptor showed a different binding interaction in comparison to the E143A mutant. This suggests that E143 residue can influence the binding interaction with the gp41 receptor. Overall, the E143 residue showed a significant role in conformation and binding to the HIV-1 receptor. These findings can be helpful in optimizing and developing HIV-1 inhibitor peptides. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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13 pages, 2924 KiB  
Article
Parameterization and Application of the General Amber Force Field to Model Fluoro Substituted Furanose Moieties and Nucleosides
by Diego E. Escalante, Courtney C. Aldrich and David M. Ferguson
Molecules 2022, 27(9), 2616; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092616 - 19 Apr 2022
Viewed by 2308
Abstract
Molecular mechanics force field calculations have historically shown significant limitations in modeling the energetic and conformational interconversions of highly substituted furanose rings. This is primarily due to the gauche effect that is not easily captured using pairwise energy potentials. In this study, we [...] Read more.
Molecular mechanics force field calculations have historically shown significant limitations in modeling the energetic and conformational interconversions of highly substituted furanose rings. This is primarily due to the gauche effect that is not easily captured using pairwise energy potentials. In this study, we present a refinement to the set of torsional parameters in the General Amber Force Field (gaff) used to calculate the potential energy of mono, di-, and gem-fluorinated nucleosides. The parameters were optimized to reproduce the pseudorotation phase angle and relative energies of a diverse set of mono- and difluoro substituted furanose ring systems using quantum mechanics umbrella sampling techniques available in the IpolQ engine in the Amber suite of programs. The parameters were developed to be internally consistent with the gaff force field and the TIP3P water model. The new set of angle and dihedral parameters and partial charges were validated by comparing the calculated phase angle probability to those obtained from experimental nuclear magnetic resonance experiments. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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21 pages, 24909 KiB  
Article
Atomistic Simulation of Lysozyme in Solutions Crowded by Tetraethylene Glycol: Force Field Dependence
by Donglin Liu, Yejie Qiu, Qing Li and Haiyang Zhang
Molecules 2022, 27(7), 2110; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27072110 - 25 Mar 2022
Cited by 1 | Viewed by 2280
Abstract
The behavior of biomolecules in crowded environments remains largely unknown due to the accuracy of simulation models and the limited experimental data for comparison. Here we chose a small crowder of tetraethylene glycol (PEG-4) to investigate the self-crowding of PEG-4 solutions and molecular [...] Read more.
The behavior of biomolecules in crowded environments remains largely unknown due to the accuracy of simulation models and the limited experimental data for comparison. Here we chose a small crowder of tetraethylene glycol (PEG-4) to investigate the self-crowding of PEG-4 solutions and molecular crowding effects on the structure and diffusion of lysozyme at varied concentrations from dilute water to pure PEG-4 liquid. Two Amber-like force fields of Amber14SB and a99SB-disp were examined with TIP3P (fast diffusivity and low viscosity) and a99SB-disp (slow diffusivity and high viscosity) water models, respectively. Compared to the Amber14SB protein simulations, the a99SB-disp model yields more coordinated water and less PEG-4 molecules, less intramolecular hydrogen bonds (HBs), more protein–water HBs, and less protein–PEG HBs as well as stronger interactions and more hydrophilic and less hydrophobic contacts with solvent molecules. The a99SB-disp model offers comparable protein–solvent interactions in concentrated PEG-4 solutions to that in pure water. The PEG-4 crowding leads to a slow-down in the diffusivity of water, PEG-4, and protein, and the decline in the diffusion from atomistic simulations is close to or faster than the hard sphere model that neglects attractive interactions. Despite these differences, the overall structure of lysozyme appears to be maintained well at different PEG-4 concentrations for both force fields, except a slightly large deviation at 370 K at low concentrations with the a99SB-disp model. This is mainly attributed to the strong intramolecular interactions of the protein in the Amber14SB force field and to the large viscosity of the a99SB-disp water model. The results indicate that the protein force fields and the viscosity of crowder solutions affect the simulation of biomolecules under crowding conditions. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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20 pages, 4781 KiB  
Article
Jusanin, a New Flavonoid from Artemisia commutata with an In Silico Inhibitory Potential against the SARS-CoV-2 Main Protease
by Yerlan M. Suleimen, Rani A. Jose, Raigul N. Suleimen, Christoph Arenz, Margarita Y. Ishmuratova, Suzanne Toppet, Wim Dehaen, Bshra A. Alsfouk, Eslam B. Elkaeed, Ibrahim H. Eissa and Ahmed M. Metwaly
Molecules 2022, 27(5), 1636; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27051636 - 01 Mar 2022
Cited by 25 | Viewed by 4177
Abstract
A new flavonoid, Jusanin, (1) has been isolated from the aerial parts of Artemisia commutata. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be 5,2′,4′-trihydroxy-6,7,5′-trimethoxyflavone. Being new in nature, the inhibition [...] Read more.
A new flavonoid, Jusanin, (1) has been isolated from the aerial parts of Artemisia commutata. The chemical structure of Jusanin has been elucidated using 1D, 2D NMR, and HR-Ms spectroscopic methods to be 5,2′,4′-trihydroxy-6,7,5′-trimethoxyflavone. Being new in nature, the inhibition potential of 1 has been estimated against SARS-CoV-2 using different in silico techniques. Firstly, molecular similarity and fingerprint studies have been conducted for Jusanin against co-crystallized ligands of eight different SARS-CoV-2 essential proteins. The studies indicated the similarity between 1 and X77, the co-crystallized ligand SARS-CoV-2 main protease (PDB ID: 6W63). To confirm the obtained results, a DFT study was carried out and indicated the similarity of (total energy, HOMO, LUMO, gap energy, and dipole moment) between 1 and X77. Accordingly, molecular docking studies of 1 against the target enzyme have been achieved and showed that 1 bonded correctly in the protein’s active site with a binding energy of −19.54 Kcal/mol. Additionally, in silico ADMET in addition to the toxicity evaluation of Jusanin against seven models have been preceded and indicated the general safety and the likeness of Jusanin to be a drug. Finally, molecular dynamics simulation studies were applied to investigate the dynamic behavior of the Mpro-Jusanin complex and confirmed the correct binding at 100 ns. In addition to 1, three other metabolites have been isolated and identified to be сapillartemisin A (2), methyl-3-[S-hydroxyprenyl]-cumarate (3), and β-sitosterol (4). Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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11 pages, 2241 KiB  
Article
Thermal Conductance of Graphene-Titanium Interface: A Molecular Simulation
by Bingxian Ou, Junxia Yan, Qinsheng Wang and Lixin Lu
Molecules 2022, 27(3), 905; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030905 - 28 Jan 2022
Cited by 4 | Viewed by 1814
Abstract
Titanium is a commonly used material in aviation, aerospace, and military applications, due to the outstanding mechanical properties of titanium and its alloys. However, its relatively low thermal conductivity restricts its extended usage. The use of graphene as a filler shows great potential [...] Read more.
Titanium is a commonly used material in aviation, aerospace, and military applications, due to the outstanding mechanical properties of titanium and its alloys. However, its relatively low thermal conductivity restricts its extended usage. The use of graphene as a filler shows great potential for the enhancement of thermal conductivity in titanium-based metal-matrix composites (MMCs). We used classical molecular dynamics (MD) simulation methods to explore the thermal conductance at the titanium–graphene (Ti/Gr) interface for its thermal boundary conductance, which plays an important role in the thermal properties of Ti-based MMCs. The effects of system size, layer number, temperature, and strain were considered. The results show that the thermal boundary conductance (TBC) decreases with an increasing layer number and reaches a plateau at n = 5. TBC falls under tensile strain and, in turn, it grows with compressive strain. The variation of TBC is explained qualitatively by the interfacial atomic vibration coupling factor. Our findings also provide insights into ways to optimize future thermal management based on Ti-based MMCs materials. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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21 pages, 38872 KiB  
Article
Expression, Purification, and Comparative Inhibition of Helicobacter pylori Urease by Regio-Selectively Alkylated Benzimidazole 2-Thione Derivatives
by Salih Osman Mohammed, Sayed H. El El Ashry, Asaad Khalid, Mohamed R. Amer, Ahmed M. Metwaly, Ibrahim H. Eissa, Eslam B. Elkaeed, Ahmed Elshobaky and Elsayed E. Hafez
Molecules 2022, 27(3), 865; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030865 - 27 Jan 2022
Cited by 19 | Viewed by 3253
Abstract
The urease enzyme has been an important target for the discovery of effective pharmacological and agricultural products. Thirteen regio-selectively alkylated benzimidazole-2-thione derivatives have been designed to carry the essential features of urease inhibitors. The urease enzyme was isolated from Helicobacter pylori as a [...] Read more.
The urease enzyme has been an important target for the discovery of effective pharmacological and agricultural products. Thirteen regio-selectively alkylated benzimidazole-2-thione derivatives have been designed to carry the essential features of urease inhibitors. The urease enzyme was isolated from Helicobacter pylori as a recombinant urease utilizing the His-tag method. The isolated enzyme was purified and characterized using chromatographic and FPLC techniques showing a maximal activity of 200 mg/mL. Additionally, the commercial Jack bean urease was purchased and included in this study for comparative and mechanistic investigations. The designed compounds were synthesized and screened for their inhibitory activity against the two ureases. Compound 2 inhibited H. pylori and Jack bean ureases with IC50 values of 0.11; and 0.26 mM; respectively. While compound 5 showed IC50 values of 0.01; and 0.29 mM; respectively. Compounds 2 and 5 were docked against Helicobacter pylori urease (PDB ID: 1E9Y; resolution: 3.00 Å) and exhibited correct binding modes with free energy (ΔG) values of −9.74 and −13.82 kcal mol−1; respectively. Further; the in silico ADMET and toxicity properties of 2 and 5 indicated their general safeties and likeness to be used as drugs. Finally, the compounds’ safety was authenticated by an in vitro cytotoxicity assay against fibroblast cells. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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22 pages, 3782 KiB  
Article
Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes
by Simona Alibrandi, Fabiana Nicita, Luigi Donato, Concetta Scimone, Carmela Rinaldi, Rosalia D’Angelo and Antonina Sidoti
Molecules 2021, 26(22), 7045; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26227045 - 22 Nov 2021
Cited by 2 | Viewed by 2071
Abstract
Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of several coding [...] Read more.
Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of several coding variants in the causative gene FMO3, that were only considered as polymorphic or benign, even if the available literature on them did not functionally explain their ineffectiveness on the encoded enzyme. Methods: Mutational analysis of 26 TMAU patients was realized by Sanger sequencing. Detected variants were, subsequently, deeply statistically and in silico characterized to determine their possible effects on the enzyme activity. To achieve this goal, a docking prediction for TMA/FMO3 and an unbinding pathway study were performed. Finally, a TMAO/TMA urine quantification by 1H-NMR spectroscopy was performed to support modelling results. Results: The FMO3 screening of all patients highlighted the presence of 17 variants distributed in 26 different haplotypes. Both non-sense and missense considered variants might impair the enzymatic kinetics of FMO3, probably reducing the interaction time between the protein catalytic site and TMA, or losing the wild-type binding site. Conclusions: Even if further functional assays will confirm our predictive results, considering the possible role of FMO3 variants with still uncertain effects, might be a relevant step towards the detection of novel scenarios in TMAU etiopathogenesis. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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19 pages, 4713 KiB  
Article
Role of Basic Surface Groups of Activated Carbon in Chlordecone and β-Hexachlorocyclohexane Adsorption: A Molecular Modelling Study
by Kenia Melchor-Rodríguez, Chayan Carmenate-Rodríguez, Anthuan Ferino-Pérez, Sarra Gaspard and Ulises J. Jáuregui-Haza
Molecules 2021, 26(22), 6969; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26226969 - 18 Nov 2021
Cited by 1 | Viewed by 1535
Abstract
The influence of nitrogen-containing surface groups (SGs) onto activated carbon (AC) over the adsorption of chlordecone (CLD) and β-hexachlorocyclohexane (β-HCH) was characterized by a molecular modelling study, considering pH (single protonated SGs) and hydration effect (up to three water molecules). The interactions of [...] Read more.
The influence of nitrogen-containing surface groups (SGs) onto activated carbon (AC) over the adsorption of chlordecone (CLD) and β-hexachlorocyclohexane (β-HCH) was characterized by a molecular modelling study, considering pH (single protonated SGs) and hydration effect (up to three water molecules). The interactions of both pollutants with amines and pyridine as basic SGs of AC were studied, applying the multiple minima hypersurface (MMH) methodology and using PM7 semiempirical Hamiltonian. Representative structures from MMH were reoptimized using the M06-2X density functional theory. The quantum theory of atoms in molecules (QTAIM) was used to characterize the interaction types in order understanding the adsorption process. A favorable association of both pesticides with the amines and pyridine SGs onto AC was observed at all pH ranges, both in the absence and presence of water molecules. However, a greater association of both pollutants with the primary amine was found under an acidic pH condition. QTAIM results show that the interactions of CLD and β-HCH with the SGs onto AC are governed by Cl···C interactions of chlorine atoms of both pesticides with the graphitic surface. Electrostatic interactions (H-bonds) were observed when water molecules were added to the systems. A physisorption mechanism is suggested for CLD and β-HCH adsorption on nitrogen-containing SGs of AC. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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27 pages, 20774 KiB  
Article
Computational Insights on the Potential of Some NSAIDs for Treating COVID-19: Priority Set and Lead Optimization
by Ayman Abo Elmaaty, Mohammed I. A. Hamed, Muhammad I. Ismail, Eslam B. Elkaeed, Hamada S. Abulkhair, Muhammad Khattab and Ahmed A. Al-Karmalawy
Molecules 2021, 26(12), 3772; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26123772 - 21 Jun 2021
Cited by 60 | Viewed by 4206
Abstract
The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that [...] Read more.
The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure–activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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7 pages, 9247 KiB  
Article
Impact of Deuteration and Temperature on Furan Ring Dynamics
by Przemyslaw Dopieralski, Iryna V. Omelchenko and Zdzislaw Latajka
Molecules 2021, 26(10), 2889; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26102889 - 13 May 2021
Viewed by 1841
Abstract
Despite significant progress in conformational analysis of cyclic molecules, the number of computational studies is still limited while most of that available in the literature data have been obtained long time ago with outdated methods. In present research, we have studied temperature driven [...] Read more.
Despite significant progress in conformational analysis of cyclic molecules, the number of computational studies is still limited while most of that available in the literature data have been obtained long time ago with outdated methods. In present research, we have studied temperature driven conformational changes of the furan ring at three different temperatures. Additionally, the effect of deuteration on the ring dynamics is discussed; in addition, the aromaticity indices following the Bird and HOMA schemes are computed along all trajectories. Our ab initio molecular dynamic simulations revealed that deuteration has changed the furan ring dynamics and the obvious consequences; in addition, the shape and size of molecule are expected to be different. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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30 pages, 4532 KiB  
Article
In Silico Studies of Some Isoflavonoids as Potential Candidates against COVID-19 Targeting Human ACE2 (hACE2) and Viral Main Protease (Mpro)
by Mohamed S. Alesawy, Abdallah E. Abdallah, Mohammed S. Taghour, Eslam B. Elkaeed, Ibrahim H. Eissa and Ahmed M. Metwaly
Molecules 2021, 26(9), 2806; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092806 - 10 May 2021
Cited by 47 | Viewed by 3018
Abstract
The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the “COVID-19” disease that has been declared by WHO as a global emergency. The pandemic, which emerged in China and widespread all over the world, has no specific treatment till now. The reported antiviral [...] Read more.
The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the “COVID-19” disease that has been declared by WHO as a global emergency. The pandemic, which emerged in China and widespread all over the world, has no specific treatment till now. The reported antiviral activities of isoflavonoids encouraged us to find out its in silico anti-SARS-CoV-2 activity. In this work, molecular docking studies were carried out to investigate the interaction of fifty-nine isoflavonoids against hACE2 and viral Mpro. Several other in silico studies including physicochemical properties, ADMET and toxicity have been preceded. The results revealed that the examined isoflavonoids bound perfectly the hACE-2 with free binding energies ranging from −24.02 to −39.33 kcal mol−1, compared to the co-crystallized ligand (−21.39 kcal mol–1). Furthermore, such compounds bound the Mpro with unique binding modes showing free binding energies ranging from −32.19 to −50.79 kcal mol–1, comparing to the co-crystallized ligand (binding energy = −62.84 kcal mol–1). Compounds 33 and 56 showed the most acceptable affinities against hACE2. Compounds 30 and 53 showed the best docking results against Mpro. In silico ADMET studies suggest that most compounds possess drug-likeness properties. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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27 pages, 3539 KiB  
Article
Zhang–Zhang Polynomials of Multiple Zigzag Chains Revisited: A Connection with the John–Sachs Theorem
by Henryk A. Witek
Molecules 2021, 26(9), 2524; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092524 - 26 Apr 2021
Cited by 4 | Viewed by 2033
Abstract
Multiple zigzag chains Zm,n of length n and width m constitute an important class of regular graphene flakes of rectangular shape. The physical and chemical properties of these basic pericondensed benzenoids can be related to their various topological invariants, conveniently [...] Read more.
Multiple zigzag chains Zm,n of length n and width m constitute an important class of regular graphene flakes of rectangular shape. The physical and chemical properties of these basic pericondensed benzenoids can be related to their various topological invariants, conveniently encoded as the coefficients of a combinatorial polynomial, usually referred to as the ZZ polynomial of multiple zigzag chains Zm,n. The current study reports a novel method for determination of these ZZ polynomials based on a hypothesized extension to John–Sachs theorem, used previously to enumerate Kekulé structures of various benzenoid hydrocarbons. We show that the ZZ polynomial of the Zm,n multiple zigzag chain can be conveniently expressed as a determinant of a Toeplitz (or almost Toeplitz) matrix of size m2×m2 consisting of simple hypergeometric polynomials. The presented analysis can be extended to generalized multiple zigzag chains Zkm,n, i.e., derivatives of Zm,n with a single attached polyacene chain of length k. All presented formulas are accompanied by formal proofs. The developed theoretical machinery is applied for predicting aromaticity distribution patterns in large and infinite multiple zigzag chains Zm,n and for computing the distribution of spin densities in biradical states of finite multiple zigzag chains Zm,n. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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20 pages, 2479 KiB  
Article
Polyphenolic Profile of Callistemon viminalis Aerial Parts: Antioxidant, Anticancer and In Silico 5-LOX Inhibitory Evaluations
by Shahenda Mahgoub, Nashwa Hashad, Sahar Ali, Reham Ibrahim, Ahmed M. Said, Fatma A. Moharram and Mohamed Mady
Molecules 2021, 26(9), 2481; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092481 - 24 Apr 2021
Cited by 10 | Viewed by 2707
Abstract
Five new compounds viz kaempferol 3-O-(4″-galloyl)-β-d-glucopyranosyl-(1‴→6″)-O-β-d-glucopyranoside (1), kaempferol 3-O-β-d-mannuronopyranoside (2), kaempferol 3-O-β-d-mannopyranoside (3), quercetin 3- [...] Read more.
Five new compounds viz kaempferol 3-O-(4″-galloyl)-β-d-glucopyranosyl-(1‴→6″)-O-β-d-glucopyranoside (1), kaempferol 3-O-β-d-mannuronopyranoside (2), kaempferol 3-O-β-d-mannopyranoside (3), quercetin 3-O-β-d-mannuronopyranoside (4), 2, 3 (S)- hexahydroxydiphenoyl]-d-glucose (5) along with fifteen known compounds were isolated from 80% aqueous methanol extract (AME) of C. viminalis. AME and compounds exerted similar or better antioxidant activity to ascorbic acid using DPPH, O2−, and NO inhibition methods. In addition, compounds 16, 4, and 7 showed cytotoxic activity against MCF-7 cell lines while 3, 7 and 16 exhibited strong activity against HepG2. An in silico analysis using molecular docking for polyphenolic compounds 2, 3, 7, 16 and 17 against human stable 5-LOX was performed and compared to that of ascorbic acid and quercetin. The binding mode as well as the enzyme-inhibitor interactions were evaluated. All compounds occupied the 5-LOX active site and showed binding affinity greater than ascorbic acid or quercetin. The data herein suggest that AME, a source of polyphenols, could be used against oxidative-stress-related disorders. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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26 pages, 3772 KiB  
Article
Synthesis, Biological Evaluation, and Molecular Modeling of Aza-Crown Ethers
by Stepan S. Basok, Igor A. Schepetkin, Andrei I. Khlebnikov, Anatoliy F. Lutsyuk, Tatiana I. Kirichenko, Liliya N. Kirpotina, Victor I. Pavlovsky, Klim A. Leonov, Darya A. Vishenkova and Mark T. Quinn
Molecules 2021, 26(8), 2225; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26082225 - 12 Apr 2021
Cited by 8 | Viewed by 3138
Abstract
Synthetic and natural ionophores have been developed to catalyze ion transport and have been shown to exhibit a variety of biological effects. We synthesized 24 aza- and diaza-crown ethers containing adamantyl, adamantylalkyl, aminomethylbenzoyl, and ε-aminocaproyl substituents and analyzed their biological effects in vitro. [...] Read more.
Synthetic and natural ionophores have been developed to catalyze ion transport and have been shown to exhibit a variety of biological effects. We synthesized 24 aza- and diaza-crown ethers containing adamantyl, adamantylalkyl, aminomethylbenzoyl, and ε-aminocaproyl substituents and analyzed their biological effects in vitro. Ten of the compounds (8, 10–17, and 21) increased intracellular calcium ([Ca2+]i) in human neutrophils, with the most potent being compound 15 (N,N’-bis[2-(1-adamantyl)acetyl]-4,10-diaza-15-crown-5), suggesting that these compounds could alter normal neutrophil [Ca2+]i flux. Indeed, a number of these compounds (i.e., 8, 10–17, and 21) inhibited [Ca2+]i flux in human neutrophils activated by N-formyl peptide (fMLF). Some of these compounds also inhibited chemotactic peptide-induced [Ca2+]i flux in HL60 cells transfected with N-formyl peptide receptor 1 or 2 (FPR1 or FPR2). In addition, several of the active compounds inhibited neutrophil reactive oxygen species production induced by phorbol 12-myristate 13-acetate (PMA) and neutrophil chemotaxis toward fMLF, as both of these processes are highly dependent on regulated [Ca2+]i flux. Quantum chemical calculations were performed on five structure-related diaza-crown ethers and their complexes with Ca2+, Na+, and K+ to obtain a set of molecular electronic properties and to correlate these properties with biological activity. According to density-functional theory (DFT) modeling, Ca2+ ions were more effectively bound by these compounds versus Na+ and K+. The DFT-optimized structures of the ligand-Ca2+ complexes and quantitative structure-activity relationship (QSAR) analysis showed that the carbonyl oxygen atoms of the N,N’-diacylated diaza-crown ethers participated in cation binding and could play an important role in Ca2+ transfer. Thus, our modeling experiments provide a molecular basis to explain at least part of the ionophore mechanism of biological action of aza-crown ethers. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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19 pages, 2413 KiB  
Article
Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity
by Naglaa M. Ahmed, Mahmoud M. Youns, Moustafa K. Soltan and Ahmed M. Said
Molecules 2021, 26(7), 1838; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26071838 - 25 Mar 2021
Cited by 21 | Viewed by 2844
Abstract
Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, [...] Read more.
Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79%) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent. Full article
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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