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Applications of Conceptual Density Functional Theory to the Chemistry and...
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Applications of Conceptual Density Functional Theory to the Chemistry and Discovery of Bioactive Compounds

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 18646

Special Issue Editors

Prof. Dr. Chia Ming Chang

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Guest Editor
Department of Soil and Environmental Sciences, National Chung Hsing University, Taichung 40227, Taiwan
Interests: nanomaterials; density functional theory
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Pratim Kumar Chattaraj

E-Mail Website
Guest Editor
Indian Institute of Technology Kharagpur, Kharagpur, India
Interests: density functional theory; chemical reactivity; non-linear dynamics; hydrogen storage; aromaticity in metal clusters
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

It is well known that bioactive compounds are beneficial to human health and have therapeutic potential. It is necessary to understand the molecular mechanism to guide the rational design of synthetic analogues with improved biological activity and pharmacological properties. From a molecular point of view, the chemical reactivity and biological activity of bioactive compounds are correlated. However, the structural characterization of bioactive compounds–biomacromolecule complexes is challenging to elucidate the structure–activity relationship.

The significance of this Special Issue lies not only in the conceptual DFT that can be used to explore the molecular mechanism, but also in providing insights from QSAR, molecular docking, and molecular dynamic and quantum chemical studies to predict and explain the inhibitory effect of natural bioactive compounds. This Special Issue covers all types of bioactive compounds and collects original research and review articles on the mechanism of action and discovery from the experimental and theoretical investigation of covalent and non-covalent interactions of bioactive compounds.

Prof. Dr. Chia Ming Chang
Prof. Dr. Pratim Kumar Chattaraj
Guest Editors

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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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

  • natural bioactive compounds
  • extraction and isolation
  • spectroscopic characterization
  • experimental biological activity
  • conceptual density functional theory
  • global and local reactivity descriptors
  • QSAR
  • molecular docking
  • molecular dynamics
  • quantum chemical methods

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Published Papers (7 papers)

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Research

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20 pages, 22942 KiB  
Article
Cu(II)-Catalysed Hydrocarboxylation of Imines Utilizing CO2 to Synthesize α-Unsaturated Aminocarboxylic Acids
by Allen T. Gordon, Eric C. Hosten and Adeniyi S. Ogunlaja
Pharmaceuticals 2022, 15(10), 1240; https://doi.org/10.3390/ph15101240 - 9 Oct 2022
Cited by 3 | Viewed by 1713
Abstract
Here, we report the Cu(II)-photocatalysed hydrocarboxylation of imines (C=N) from a series of synthesized Schiff Base derivatives, namely (E)-1-(4-((4-methylbenzylidene)amino)phenyl)ethanone, (E)-1-(3-((5-bromo-2-hydroxybenzylidene)amino)phenyl)ethanone, (E)-4-((5-bromo-2-hydroxybenzylidene)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one, and (E)-1,5-dimethyl-4-((4-methylbenzylidene)amino)-2-phenyl-1H-pyrazol-3(2H)-one, with carbon dioxide (CO2) to generate disubstituted amino acids. Under mild conditions (atmospheric pressure of [...] Read more.
Here, we report the Cu(II)-photocatalysed hydrocarboxylation of imines (C=N) from a series of synthesized Schiff Base derivatives, namely (E)-1-(4-((4-methylbenzylidene)amino)phenyl)ethanone, (E)-1-(3-((5-bromo-2-hydroxybenzylidene)amino)phenyl)ethanone, (E)-4-((5-bromo-2-hydroxybenzylidene)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one, and (E)-1,5-dimethyl-4-((4-methylbenzylidene)amino)-2-phenyl-1H-pyrazol-3(2H)-one, with carbon dioxide (CO2) to generate disubstituted amino acids. Under mild conditions (atmospheric pressure of CO2, room temperature, and 30 W Blue LED light), good to excellent yields confirming the formation of substituted amino acid unsaturated acid derivatives were obtained. Single crystal X-ray diffraction (SC-XRD) and UV-Vis diffuse reflectance spectroscopy (UV-Vis-DRS) confirmed the square pyramidal geometry of the Cu(II) photocatalyst. Docking and DFT calculations of the substituted amino acid unsaturated acid derivatives showed their potential as antimicrobial molecules. Full article
(This article belongs to the Special Issue Applications of Conceptual Density Functional Theory to the Chemistry and Discovery of Bioactive Compounds)
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34 pages, 5348 KiB  
Article
The IQA Energy Partition in a Drug Design Setting: A Hepatitis C Virus RNA-Dependent RNA Polymerase (NS5B) Case Study
by César A. Zapata-Acevedo and Paul L. A. Popelier
Pharmaceuticals 2022, 15(10), 1237; https://doi.org/10.3390/ph15101237 - 8 Oct 2022
Cited by 2 | Viewed by 1773
Abstract
The interaction of the thumb site II of the NS5B protein of hepatitis C virus and a pair of drug candidates was studied using a topological energy decomposition method called interacting quantum atoms (IQA). The atomic energies were then processed by the relative [...] Read more.
The interaction of the thumb site II of the NS5B protein of hepatitis C virus and a pair of drug candidates was studied using a topological energy decomposition method called interacting quantum atoms (IQA). The atomic energies were then processed by the relative energy gradient (REG) method, which extracts chemical insight by computation based on minimal assumptions. REG reveals the most important IQA energy contributions, by atom and energy type (electrostatics, sterics, and exchange–correlation), that are responsible for the behaviour of the whole system, systematically from a short-range ligand–pocket interaction until a distance of approximately 22 Å. The degree of covalency in various key interatomic interactions can be quantified. No exchange–correlation contribution is responsible for the changes in the energy profile of both pocket–ligand systems investigated in the ligand–pocket distances equal to or greater than that of the global minimum. Regarding the hydrogen bonds in the system, a “neighbour effect” was observed thanks to the REG method, which states that a carbon atom would rather not have its covalent neighbour oxygen form a hydrogen bond. The combination of IQA and REG enables the automatic identification of the pharmacophore in the ligands. The coarser Interacting Quantum Fragments (IQF) enables the determination of which amino acids of the pocket contribute most to the binding and the type of energy of said binding. This work is an example of the contribution topological energy decomposition methods can make to fragment-based drug design. Full article
(This article belongs to the Special Issue Applications of Conceptual Density Functional Theory to the Chemistry and Discovery of Bioactive Compounds)
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15 pages, 825 KiB  
Article
From Density Functional Theory to Conceptual Density Functional Theory and Biosystems
by Paul Geerlings
Pharmaceuticals 2022, 15(9), 1112; https://doi.org/10.3390/ph15091112 - 6 Sep 2022
Cited by 19 | Viewed by 3485
Abstract
The position of conceptual density functional theory (CDFT) in the history of density functional theory (DFT) is sketched followed by a chronological report on the introduction of the various DFT descriptors such as the electronegativity, hardness, softness, Fukui function, local version of softness [...] Read more.
The position of conceptual density functional theory (CDFT) in the history of density functional theory (DFT) is sketched followed by a chronological report on the introduction of the various DFT descriptors such as the electronegativity, hardness, softness, Fukui function, local version of softness and hardness, dual descriptor, linear response function, and softness kernel. Through a perturbational approach they can all be characterized as response functions, reflecting the intrinsic reactivity of an atom or molecule upon perturbation by a different system, including recent extensions by external fields. Derived descriptors such as the electrophilicity or generalized philicity, derived from the nature of the energy vs. N behavior, complete this picture. These descriptors can be used as such or in the context of principles such as Sanderson’s electronegativity equalization principle, Pearson’s hard and soft acids and bases principle, the maximum hardness, and more recently, the minimum electrophilicity principle. CDFT has known an ever-growing use in various subdisciplines of chemistry: from organic to inorganic chemistry, from polymer to materials chemistry, and from catalysis to nanotechnology. The increasing size of the systems under study has been coped with thanks to methodological evolutions but also through the impressive evolution in software and hardware. In this flow, biosystems entered the application portfolio in the past twenty years with studies varying (among others) from enzymatic catalysis to biological activity and/or the toxicity of organic molecules and to computational peptidology. On the basis of this evolution, one can expect that “the best is yet to come”. Full article
(This article belongs to the Special Issue Applications of Conceptual Density Functional Theory to the Chemistry and Discovery of Bioactive Compounds)
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15 pages, 2372 KiB  
Article
A Density Functional Theory and Information-Theoretic Approach Study of Interaction Energy and Polarizability for Base Pairs and Peptides
by Dongbo Zhao, Shubin Liu and Dahua Chen
Pharmaceuticals 2022, 15(8), 938; https://doi.org/10.3390/ph15080938 - 28 Jul 2022
Cited by 17 | Viewed by 2126
Abstract
Using density functional theory (DFT) and the information-theoretic approach (ITA) quantities to appreciate the energetics and properties of biopolymers is still an unaccomplished and ongoing task. To this end, we studied the building blocks of nucleic acid base pairs and small peptides. For [...] Read more.
Using density functional theory (DFT) and the information-theoretic approach (ITA) quantities to appreciate the energetics and properties of biopolymers is still an unaccomplished and ongoing task. To this end, we studied the building blocks of nucleic acid base pairs and small peptides. For base pairs, we have dissected the relative importance of energetic components by using two energy partition schemes in DFT. Our results convincingly show that the exchange-correlation effect predominantly governs the molecular stability of base pairs while the electrostatic potential plays a minor but indispensable role, and the steric effect is trivial. Furthermore, we have revealed that simple density-based ITA functions are in good relationships with molecular polarizabilities for a series of 30 hydrogen-bonded base pairs and all 20 natural α-amino acids, 400 dipeptides, and 8000 tripeptides. Based on these lines, one can easily predict the molecular polarizabilities of larger peptides, even proteins as long as the total molecular wavefunction is available, rather than solving the computationally demanding coupled-perturbed Hartree–Fock (CPHF) equation or its DFT counterpart coupled-perturbed Kohn–Sham (CPKS) equation. Full article
(This article belongs to the Special Issue Applications of Conceptual Density Functional Theory to the Chemistry and Discovery of Bioactive Compounds)
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15 pages, 3878 KiB  
Article
A Quantum Chemical Deep-Dive into the π-π Interactions of 3-Methylindole and Its Halogenated Derivatives—Towards an Improved Ligand Design and Tryptophan Stacking
by Ruben Van Lommel, Tom Bettens, Thomas M. A. Barlow, Jolien Bertouille, Steven Ballet and Frank De Proft
Pharmaceuticals 2022, 15(8), 935; https://doi.org/10.3390/ph15080935 - 28 Jul 2022
Cited by 5 | Viewed by 3110
Abstract
Non-covalent π-π stacking interactions often play a key role in the stability of the secondary and tertiary structures of peptides and proteins, respectively, and can be a means of ensuring the binding of ligands within protein and enzyme binding sites. It is generally [...] Read more.
Non-covalent π-π stacking interactions often play a key role in the stability of the secondary and tertiary structures of peptides and proteins, respectively, and can be a means of ensuring the binding of ligands within protein and enzyme binding sites. It is generally accepted that minor structural changes to the aromatic ring, such as substitution, can have a large influence on these interactions. Nevertheless, a thorough understanding of underpinning phenomena guiding these key interactions is still limited. This is especially true for larger aromatic structures. To expand upon this knowledge, elaborate ab initio calculations were performed to investigate the effect of halogenation on the stability of 3-methylindole stacking. 3-Methylindole served as a representation of the tryptophan side chain, and is a frequently used motif in drug design and development. Moreover, an expression is derived that is able to accurately predict the interaction stability of stacked halogenated 3-methylindole dimers as well as halogenated toluene dimers, based on monomer level calculated DFT descriptors. We aim for this expression to provide the field with a straightforward and reliable method to assess the effect of halogenation on the π-π stacking interactions between aromatic scaffolds. Full article
(This article belongs to the Special Issue Applications of Conceptual Density Functional Theory to the Chemistry and Discovery of Bioactive Compounds)
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10 pages, 1805 KiB  
Article
Virtual Prospection of Marine Cyclopeptides as Therapeutics by Means of Conceptual DFT and Computational ADMET
by Norma Flores-Holguín, Juan Frau and Daniel Glossman-Mitnik
Pharmaceuticals 2022, 15(5), 509; https://doi.org/10.3390/ph15050509 - 22 Apr 2022
Cited by 6 | Viewed by 2228
Abstract
Bioactive peptides are chemical compounds created through the covalent bonding of amino acids, known as amide or peptide bonds. Due to their unusual chemistry and various biological effects, marine bioactive peptides have garnered considerable research. The effectiveness of a bioactive marine peptide is [...] Read more.
Bioactive peptides are chemical compounds created through the covalent bonding of amino acids, known as amide or peptide bonds. Due to their unusual chemistry and various biological effects, marine bioactive peptides have garnered considerable research. The effectiveness of a bioactive marine peptide is attributed to its structural features, such as amino acid content and sequence, which vary depending on the degree of action. Cyclic peptides combine several favorable properties such as good binding affinity, target selectivity and low toxicity that render them an attractive modality for the development of therapeutics. The apratoxins are a class of molecules formed by a series of cyclic depsipeptides with potent cytotoxic activities. The objective of this research is to pursue a computational prospection of the molecular structures and properties of several cylopeptides of marine origin with potential therapeutic applications. The methodology will be based on the determination of the chemical reactivity descriptors of the studied molecules through the consideration of the Conceptual DFT model and validation of a particular model chemistry, MN12SX/Def2TZVP/H2O. These studies will be complemented by a determination of the pharmacokinetics and ADMET parameters by resorting to certain cheminformatics tools. Full article
(This article belongs to the Special Issue Applications of Conceptual Density Functional Theory to the Chemistry and Discovery of Bioactive Compounds)
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Review

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16 pages, 2583 KiB  
Review
Quantitative Structure–Toxicity Relationship in Bioactive Molecules from a Conceptual DFT Perspective
by Ranita Pal, Shanti Gopal Patra and Pratim Kumar Chattaraj
Pharmaceuticals 2022, 15(11), 1383; https://doi.org/10.3390/ph15111383 - 10 Nov 2022
Cited by 6 | Viewed by 2527
Abstract
The preclinical drug discovery stage often requires a large amount of costly and time-consuming experiments using huge sets of chemical compounds. In the last few decades, this process has undergone significant improvements by the introduction of quantitative structure-activity relationship (QSAR) modelling that uses [...] Read more.
The preclinical drug discovery stage often requires a large amount of costly and time-consuming experiments using huge sets of chemical compounds. In the last few decades, this process has undergone significant improvements by the introduction of quantitative structure-activity relationship (QSAR) modelling that uses a certain percentage of experimental data to predict the biological activity/property of compounds with similar structural skeleton and/or containing a particular functional group(s). The use of machine learning tools along with it has made life even easier for pharmaceutical researchers. Here, we discuss the toxicity of certain sets of bioactive compounds towards Pimephales promelas and Tetrahymena pyriformis in terms of the global conceptual density functional theory (CDFT)-based descriptor, electrophilicity index (ω). We have compared the results with those obtained by using the commonly used hydrophobicity parameter, logP (where P is the n-octanol/water partition coefficient), considering the greater ease of computing the ω descriptor. The Human African trypanosomiasis (HAT) curing activity of 32 pyridyl benzamide derivatives is also studied against Tryphanosoma brucei. In this review article, we summarize these multiple linear regression (MLR)-based QSAR studies in terms of electrophilicity (ω, ω2) and hydrophobicity (logP, (logP)2) parameters. Full article
(This article belongs to the Special Issue Applications of Conceptual Density Functional Theory to the Chemistry and Discovery of Bioactive Compounds)
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