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Molecular Modeling: Advancements and Applications II

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

Deadline for manuscript submissions: closed (31 May 2024) | Viewed by 22823

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Prof. Dr. Teobald Kupka

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Faculty of Chemistry, Uniwersytet Opolski, Opole, Poland
Interests: NMR; IR/Raman; spectroscopy; theoretical modeling; nanotechnology; anticancer and antibacterial drugs
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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 recent decades, both in basic and applied sciences, we have witnessed an avalanche of novel methods and applications of molecular modeling in chemistry, pharmacy, and material sciences.

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

Structure and property prediction of new molecular systems.
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 calculations 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.

Prof. Dr. Teobald Kupka
Guest Editor

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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.

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Keywords

quantum mechanics
molecular mechanics (MM)
molecular dynamics (MD)
semiempirical 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 noncovalent interactions
large molecular systems
IR, Raman, and NMR
drug design
nanomaterials and nanotechnology
material sciences

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Published Papers (11 papers)

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Research

28 pages, 2666 KiB

Open AccessArticle

Synthesis, Docking, and Machine Learning Studies of Some Novel Quinolinesulfonamides–Triazole Hybrids with Anticancer Activity

by Krzysztof Marciniec, Justyna Nowakowska, Elwira Chrobak, Ewa Bębenek and Małgorzata Latocha

Molecules 2024, 29(13), 3158; https://doi.org/10.3390/molecules29133158 - 2 Jul 2024

Viewed by 1241

Abstract

In the presented work, a series of 22 hybrids of 8-quinolinesulfonamide and 1,4-disubstituted triazole with antiproliferative activity were designed and synthesised. The title compounds were designed using molecular modelling techniques. For this purpose, machine-learning, molecular docking, and molecular dynamics methods were used. Calculations of the pharmacokinetic parameters (connected with absorption, distribution, metabolism, excretion, and toxicity) of the hybrids were also performed. The new compounds were synthesised via a copper-catalysed azide–alkyne cycloaddition reaction (CuAAC). 8-N-Methyl-N-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}quinolinesulfonamide was identified in in silico studies as a potential strong inhibitor of Rho-associated protein kinase and as a compound that has an appropriate pharmacokinetic profile. The results obtained from in vitro experiments confirm the cytotoxicity of derivative 9b in four selected cancer cell lines and the lack of cytotoxicity of this derivative towards normal cells. The results obtained from silico and in vitro experiments indicate that the introduction of another quinolinyl fragment into the inhibitor molecule may have a significant impact on increasing the level of cytotoxicity toward cancer cells and indicate a further direction for future research in order to find new substances suitable for clinical applications in cancer treatment. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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27 pages, 7268 KiB

Open AccessArticle

Integrating Explicit and Implicit Fullerene Models into UNRES Force Field for Protein Interaction Studies

by Natalia H. Rogoża, Magdalena A. Krupa, Pawel Krupa and Adam K. Sieradzan

Molecules 2024, 29(9), 1919; https://doi.org/10.3390/molecules29091919 - 23 Apr 2024

Cited by 1 | Viewed by 1977

Abstract

Fullerenes, particularly C₆₀, exhibit unique properties that make them promising candidates for various applications, including drug delivery and nanomedicine. However, their interactions with biomolecules, especially proteins, remain not fully understood. This study implements both explicit and implicit C₆₀ models into the UNRES coarse-grained force field, enabling the investigation of fullerene–protein interactions without the need for restraints to stabilize protein structures. The UNRES force field offers computational efficiency, allowing for longer timescale simulations while maintaining accuracy. Five model proteins were studied: FK506 binding protein, HIV-1 protease, intestinal fatty acid binding protein, PCB-binding protein, and hen egg-white lysozyme. Molecular dynamics simulations were performed with and without C₆₀ to assess protein stability and investigate the impact of fullerene interactions. Analysis of contact probabilities reveals distinct interaction patterns for each protein. FK506 binding protein (1FKF) shows specific binding sites, while intestinal fatty acid binding protein (1ICN) and uteroglobin (1UTR) exhibit more generalized interactions. The explicit C₆₀ model shows good agreement with all-atom simulations in predicting protein flexibility, the position of C₆₀ in the binding pocket, and the estimation of effective binding energies. The integration of explicit and implicit C₆₀ models into the UNRES force field, coupled with recent advances in coarse-grained modeling and multiscale approaches, provides a powerful framework for investigating protein–nanoparticle interactions at biologically relevant scales without the need to use restraints stabilizing the protein, thus allowing for large conformational changes to occur. These computational tools, in synergy with experimental techniques, can aid in understanding the mechanisms and consequences of nanoparticle–biomolecule interactions, guiding the design of nanomaterials for biomedical applications. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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15 pages, 1433 KiB

Open AccessArticle

DFT Studies of the Activity and Reactivity of Limonene in Comparison with Selected Monoterpenes

by Katarzyna Rydel-Ciszek

Molecules 2024, 29(7), 1579; https://doi.org/10.3390/molecules29071579 - 1 Apr 2024

Cited by 1 | Viewed by 1381

Abstract

Nowadays, the effective processing of natural monoterpenes that constitute renewable biomass found in post-production waste into products that are starting materials for the synthesis of valuable compounds is a way to ensure independence from non-renewable fossil fuels and can contribute to reducing global carbon dioxide emissions. The presented research aims to determine, based on DFT calculations, the activity and reactivity of limonene, an organic substrate used in previous preparative analyses, in comparison to selected monoterpenes such as cymene, pinene, thymol, and menthol. The influence of the solvent model was also checked, and the bonds most susceptible to reaction were determined in the examined compounds. With regard to E_HOMO, it was found that limonene reacts more easily than cymene or menthol but with more difficultly than thymol and pienene. The analysis of the global chemical reactivity descriptors “locates” the reactivity of limonene in the middle of the studied monoterpenes. It was observed that, among the tested compounds, the most reactive compound is thymol, while the least reactive is menthol. The demonstrated results can be a reference point for experimental work carried out using the discussed compounds, to focus research on those with the highest reactivity. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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14 pages, 3861 KiB

Open AccessArticle

N-Methyl- and N-Phenylpiperazine Functionalized Styryl Dyes Inside Cucurbiturils: Theoretical Assessment of the Factors Governing the Host–Guest Recognition

by Nikoleta Kircheva, Vladislava Petkova, Stefan Dobrev, Valya Nikolova, Silvia Angelova and Todor Dudev

Molecules 2023, 28(24), 8130; https://doi.org/10.3390/molecules28248130 - 16 Dec 2023

Cited by 1 | Viewed by 1250

Abstract

The family of cucurbiturils (CBs), the unique pumpkin-shaped macrocycles, has received great attention over the past four decades owing to their remarkable recognition properties. They have found diverse applications including biosensing and drug delivery technologies. The cucurbituril complexation of guest molecules can modulate their pK_as, improve their solubility in aqueous solution, and reduce the adverse effects of the drugs, as well as enhance the stability and/or enable targeted delivery of the drug molecule. Employing twelve cationic styryl dyes with N-methyl- and N-phenylpiperazine functionality as probes, we attempted to understand the factors that govern the host–guest complexation of such molecules within CB[7] and CB[8] host systems. Various key factors determining the process were recognized, such as the pH and dielectric constant of the medium, the cavity size of the host, the chemical characteristics of the substituents in the guest entity, and the presence/absence of metal cations. The presented results add to our understanding (at the molecular level) of the mechanism of encapsulation of styryl dyes by cucurbiturils, thus shedding new light on various aspects of the intriguing complexation chemistry and the underlying recognition processes. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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14 pages, 3216 KiB

Open AccessArticle

Towards Computational Modeling of Ligand Binding to the ILPR G-Quadruplex

by Xiaotong Zhang, John Barrow, Tanja van Mourik and Michael Bühl

Molecules 2023, 28(8), 3447; https://doi.org/10.3390/molecules28083447 - 13 Apr 2023

Viewed by 2218

Abstract

Using a combination of unconstrained and constrained molecular dynamics simulations, we have evaluated the binding affinities between two porphyrin derivatives (TMPyP4 and TEGPy) and the G-quadruplex (G4) of a DNA fragment modeling the insulin-linked polymorphic region (ILPR). Refining a well-established potential of mean force (PMF) approach to selections of constraints based on root-mean-square fluctuations results in an excellent agreement between the calculated and observed absolute free binding energy of TMPyP4. The binding affinity of IPLR-G4 toward TEGPy is predicted to be higher than that toward TMPyP4 by 2.5 kcal/mol, which can be traced back to stabilization provided by the polyether side chains of TMPyP4 that can nestle into the grooves of the quadruplex and form hydrogen bonds through the ether oxygen atoms. Because our refined methodology can be applied to large ligands with high flexibility, the present research opens an avenue for further ligand design in this important area. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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15 pages, 3199 KiB

Open AccessArticle

The Interplay of Weakly Coordinating Anions and the Mechanical Bond: A Systematic Study of the Explicit Influence of Counterions on the Properties of (Pseudo)rotaxanes

by J. Felix Witte, Janos Wasternack, Shenquan Wei, Christoph A. Schalley and Beate Paulus

Molecules 2023, 28(7), 3077; https://doi.org/10.3390/molecules28073077 - 30 Mar 2023

Cited by 4 | Viewed by 2389

Abstract

Weakly coordinating anions (WCAs) have attracted much attention in recent years due to their ability to stabilise highly reactive cations. It may well be argued, however, that a profound understanding of what truly defines a WCA is still lacking, and systematic studies to unravel counterion effects are scarce. In this work, we investigate a supramolecular pseudorotaxane formation reaction, subject to a selection of anions, ranging from strongly to weakly coordinating, which not only aids in fostering our knowledge about anion coordination properties, but also provides valuable theoretical insight into the nature of the mechanical bond. We employ state-of-the-art DFT-based methods and tools, combined with isothermal calorimetry and

^{1}

H NMR experiments, to compute anion-dependent Gibbs free association energies

Δ G_{a}

, as well as to evaluate intermolecular interactions. We find correlations between

Δ G_{a}

and the anions’ solvation energies, which are exploited to calculate physico-chemical reaction parameters in the context of coordinating anions. Furthermore, we show that the binding situation within the (pseudo)rotaxanes can be mostly understood by straight-forward electrostatic considerations. However, quantum-chemical effects such as dispersion and charge-transfer interactions become more and more relevant when WCAs are employed. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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12 pages, 2640 KiB

Open AccessArticle

MD Simulation Reveals Regulation of Mechanical Force and Extracellular Domain 2 on Binding of DNAM-1 to CD155

by Liping Fang, Yang Zhao, Pei Guo, Ying Fang and Jianhua Wu

Molecules 2023, 28(6), 2847; https://doi.org/10.3390/molecules28062847 - 21 Mar 2023

Cited by 1 | Viewed by 1491

Abstract

Two extracellular domains of the adhesive receptor DNAM-1 are involved in various cellular biological processes through binding to ligand CD155, usually under a mechano-microenvironment. The first extracellular domain (D1) plays a key role in recognition, but the function of the second extracellular domain (D2) and effects of force on the interaction of DNAM-1 with CD155 remain unclear. We herein studied the interaction of DNAM-1 with CD155 by performing steered molecular dynamics (MD) simulations, and observed the roles of tensile force and D2 on the affinity of DNAM-1 to CD155. The results showed that D2 improved DNAM-1 affinity to CD155; the DNAM-1/CD155 complex had a high mechanical strength and a better mechanical stability for its conformational conservation either at pulling with constant velocity or under constant tensile force (≤100 pN); the catch–slip bond transition governed CD155 dissociation from DNAM-1; and, together with the newly assigned key residues in the binding site, force-induced conformation changes should be responsible for the mechanical regulation of DNAM-1′s affinity to CD155. This work provided a novel insight in understanding the mechanical regulation mechanism and D2 function in the interaction of DNAM-1 with CD155, as well as their molecular basis, relevant transmembrane signaling, and cellular immune responses under a mechano-microenvironment. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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11 pages, 2423 KiB

Open AccessArticle

A Molecular Dynamics Simulation for Thermal Activation Process in Covalent Bond Dissociation of a Crosslinked Thermosetting Polymer

by Naoki Yamada, Yutaka Oya, Nobuhiko Kato, Kazuki Mori and Jun Koyanagi

Molecules 2023, 28(6), 2736; https://doi.org/10.3390/molecules28062736 - 17 Mar 2023

Cited by 5 | Viewed by 2292

Abstract

A novel algorithm for covalent bond dissociation is developed to accurately predict fracture behavior of thermosetting polymers via molecular dynamics simulation. This algorithm is based on the Monte Carlo method that considers the difference in local strain and bond-dissociation energies to reproduce a thermally activated process in a covalent bond dissociation. This study demonstrates the effectiveness of this algorithm in predicting the stress–strain relationship of fully crosslinked thermosetting polymers under uniaxial tensile conditions. Our results indicate that the bond-dissociation energy plays an important role in reproducing the brittle fracture behavior of a thermosetting polymer by affecting the number of covalent bonds that are dissociated simultaneously. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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13 pages, 1239 KiB

Open AccessArticle

Trapping of Small Molecules within Single or Double Cyclo[18]carbon Rings

by Natasza Trzęsowska, Rafał Wysokiński, Mariusz Michalczyk, Wiktor Zierkiewicz and Steve Scheiner

Molecules 2023, 28(5), 2157; https://doi.org/10.3390/molecules28052157 - 25 Feb 2023

Cited by 2 | Viewed by 1859

Abstract

The encapsulation of a set of small molecules, H₂, CO, CO₂, SO₂, and SO₃, by a circular C₁₈ ring is investigated by quantum calculations. These ligands lie near the center of the ring but, with the exception of H₂, are disposed roughly perpendicular to the ring plane. Their binding energies with the C₁₈ vary from 1.5 kcal/mol for H₂ up to 5.7 kcal/mol for SO₂, and the bonding is dominated by dispersive interactions spread over the entire ring. The binding of these ligands on the outside of the ring is weaker but allows the opportunity for each to bond covalently with the ring. A pair of C₁₈ units lie parallel to one another. This pair can bind each of these ligands in the area between them with only small perturbations of the double ring geometry. The binding energies of these ligands to this double ring configuration are amplified by some 50% compared to the single ring systems. The presented data concerning the trapping of small molecules may have larger implications regarding hydrogen storage or air pollution reduction. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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21 pages, 3166 KiB

Open AccessArticle

Identification of Antiviral Compounds against Monkeypox Virus Profilin-like Protein A42R from Plantago lanceolata

by Leena H. Bajrai, Azzah S. Alharbi, Mai M. El-Day, Abrar G. Bafaraj, Vivek Dhar Dwivedi and Esam I. Azhar

Molecules 2022, 27(22), 7718; https://doi.org/10.3390/molecules27227718 - 9 Nov 2022

Cited by 10 | Viewed by 2642

Abstract

Infections caused by the monkeypox virus (MPXV) have continued to be transmitted significantly in recent years. However, understanding the transmission mechanism, risk factors, and consequences of infection are still limited. Structure-based drug design for MPXV is at an early stage due to the availability of protein structures that have been determined experimentally. However, the structure of the A42R profilin-like protein of MPXV has been solved and submitted to the structure database. This study illustrated an in silico structure-based approach to identify the potential hit compound against A42R of MPXV. Here, 65 Plantago lanceolata compounds were computationally screened against A42R of MPXV. Virtual screening identified top five hits (i) Luteolin 7,3′-Diglucuronide (PubChem ID: 44258091), (ii) Luteolin 7-Glucuronide-3′-Glucoside (PubChem ID: 44258090), (iii) Plantagoside (PubChem ID: 174157), (iv) Narcissoside (PubChem ID: 5481663), and (v) (AlphaE,8S,9R)-N-(3,4-Dihydroxyphenethyl)-8-[(3,4-Dihydroxyphenethyl)Carbamoyl]-9-(1,3-Benzodioxole-5-Yl)-3aalpha,7aalpha-Ethano-1,3-Benzodioxole-5-Acrylamide (PubChem ID: 101131595), with binding energy <−9.0 kcal/mol that was further validated by re-docking and molecular dynamic (MD) simulation. Interaction analysis of re-docked poses confirmed the binding of these top hits to the A42R protein as reported in the reference compound, including active residues ARG114, ARG115, and ARG119. Further, MD simulation and post-simulation analysis support Plantagoside and Narcissoside for substantial stability in the binding pocket of viral protein contributed by hydrogen and hydrophobic interactions. The compounds can be considered for further optimisation and in vitro experimental validation for anti-monkeypox drug development. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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29 pages, 13826 KiB

Open AccessArticle

New Anticancer Theobromine Derivative Targeting EGFR^WT and EGFR^T790M: Design, Semi-Synthesis, In Silico, and In Vitro Anticancer Studies

by Eslam B. Elkaeed, Reda G. Yousef, Hazem Elkady, Aisha A. Alsfouk, Dalal Z. Husein, Ibrahim M. Ibrahim, Ahmed M. Metwaly and Ibrahim H. Eissa

Molecules 2022, 27(18), 5859; https://doi.org/10.3390/molecules27185859 - 9 Sep 2022

Cited by 30 | Viewed by 2814

Abstract

Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with the catalytic pocket of EGFR. Molecular docking against wild (EGFR^WT; PDB: 4HJO) and mutant (EGFR^T790M; PDB: 3W2O) types of EGFR-TK indicated that the designed theobromine derivative had the potential to bind to that pocket as an antiangiogenic inhibitor. The MD and MM-GBSA experiments identified the exact binding with optimum energy and dynamics. Additionally, the DFT calculations studied electrostatic potential, stability, and total electron density of the designed theobromine derivative. Both in silico ADMET and toxicity analyses demonstrated its general likeness and safety. We synthesized the designed theobromine derivative (compound XI) which showed an IC₅₀ value of 17.23 nM for EGFR inhibition besides IC₅₀ values of 21.99 and 22.02 µM for its cytotoxicity against A549 and HCT-116 cell lines, respectively. Interestingly, compound XI expressed a weak cytotoxic potential against the healthy W138 cell line (IC₅₀ = 49.44 µM, 1.6 times safer than erlotinib), exhibiting the high selectivity index of 2.2. Compound XI arrested the growth of A549 at the G2/M stage and increased the incidence of apoptosis. Full article

(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications II)

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