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Conformations and Physicochemical Properties of Biological Ligands in Various Environments
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Conformations and Physicochemical Properties of Biological Ligands in Various Environments

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Physical Chemistry and Chemical Physics".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 19165

Special Issue Editor

Prof. Dr. Jean-Yves Le Questel

E-Mail Website
Guest Editor
Université de Nantes, CNRS, CEISAM UMR 6230, F-44000 Nantes, France
Interests: molecular modelling; theoretical chemistry; modeling of the structural and energetic features of intermolecular interactions (hydrogen bonding and sigma-hole interactions); interactions in biomolecular complexes: ligand-receptor; insecticides-nAChRs (nicotinic acetylcholine receptors); protein-protein

Special Issue Information

Dear Colleagues,

Understanding and describing the conformational landscape of druglike molecules is important in medicinal chemistry for the discovery of lead compounds and their optimization. The challenge of this quest is related to the fact that the conformational features of druglike molecules are strongly dependent on their environments. Furthermore, the biactive conformation of a ligand inside the target binding pocket is noticeably affected by induced fit. Therefore, the combination of experimental (from gas phase, solution to solid state environments) and theoretical approaches is a powerful means to decipher the effects underlying the conformational preferences observed.

The aim of this Special Issue is to gather contributions dedicated to this field. The invited papers will describe the conformational behavior of biological ligands, using a combination of experimental methods (for example either x-ray, NMR or gas phase studies) and quantum chemistry calculations, used to rationalize, through relevant descriptors, the observed preferences. Papers based on experimental observations in crystallographic databases compared with the results obtained through computational chemistry calculations are also welcome.

Prof. Jean-Yves Le Questel
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • three dimensional structure
  • conformational analysis
  • intramolecular/intermolecular interactions
  • hydrogen bonds
  • quantum chemistry
  • theoretical descriptors

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 193 KiB  
Editorial
Conformations and Physicochemical Properties of Biological Ligands in Various Environments
by Jean-Yves Le Questel
Int. J. Mol. Sci. 2023, 24(11), 9630; https://doi.org/10.3390/ijms24119630 - 01 Jun 2023
Viewed by 745
Abstract
An accurate description of the conformational behavior of drug-like molecules is often a prerequisite for a comprehensive understanding of their behavior, in particular in the targeted receptor surroundings [...] Full article
(This article belongs to the Special Issue Conformations and Physicochemical Properties of Biological Ligands in Various Environments)

Research

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17 pages, 4735 KiB  
Article
Solvates of New Arylpiperazine Salicylamide Derivative-a Multi-Technique Approach to the Description of 5 HTR Ligand Structure and Interactions
by Edyta Pindelska, Anna Marczewska-Rak, Jolanta Jaśkowska and Izabela D. Madura
Int. J. Mol. Sci. 2021, 22(9), 4992; https://doi.org/10.3390/ijms22094992 - 08 May 2021
Cited by 3 | Viewed by 2025
Abstract
A new ligand for 5-HT1A and 5-HT7 receptors, an arylpiperazine salicylamide derivative with an inflexible spacer, is investigated to identify preferred fragments capable of creating essential intermolecular interactions in different solvates. To fully identify and characterize the obtained crystalline materials, various methods including [...] Read more.
A new ligand for 5-HT1A and 5-HT7 receptors, an arylpiperazine salicylamide derivative with an inflexible spacer, is investigated to identify preferred fragments capable of creating essential intermolecular interactions in different solvates. To fully identify and characterize the obtained crystalline materials, various methods including powder and single-crystal X-ray diffraction, solid-state NMR, and thermal analysis were employed, supplemented by periodic ab initio calculations. The molecular conformation in different solvates, types, and hierarchy of intermolecular interactions as well as the crystal packing were investigated to provide data for future research focused on studying protein–ligand interactions. Based on various methods of crystal structure analysis, including the interaction energy calculation and programs using an artificial neural network, a salicylamide fragment was found to be crucial for intermolecular contacts, mostly of dispersion and electrostatic character. A supramolecular 2D kite-type layer of {4,4} topology was found to form in crystals. The closed voids between layers contain disordered solvents, very weakly interacting with the molecule and the layer. It has been postulated that the separation of the layers might be influenced by an increase in temperature or the size of the solvent; hence, only methanol and ethanol hemi-solvates could be obtained from a series of various alcohols. Full article
(This article belongs to the Special Issue Conformations and Physicochemical Properties of Biological Ligands in Various Environments)
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16 pages, 2906 KiB  
Article
Intermolecular Interactions in Crystal Structures of Imatinib-Containing Compounds
by Anna V. Vologzhanina, Ivan E. Ushakov and Alexander A. Korlyukov
Int. J. Mol. Sci. 2020, 21(23), 8970; https://doi.org/10.3390/ijms21238970 - 26 Nov 2020
Cited by 14 | Viewed by 2703
Abstract
Imatinib, one of the most used therapeutic agents to treat leukemia, is an inhibitor that specifically blocks the activity of tyrosine kinases. The molecule of imatinib is flexible and contains several functional groups able to take part in H-bonding and hydrophobic interactions. Analysis [...] Read more.
Imatinib, one of the most used therapeutic agents to treat leukemia, is an inhibitor that specifically blocks the activity of tyrosine kinases. The molecule of imatinib is flexible and contains several functional groups able to take part in H-bonding and hydrophobic interactions. Analysis of molecular conformations for this drug was carried out using density functional theory calculations of rotation potentials along single bonds and by analyzing crystal structures of imatinib-containing compounds taken from the Cambridge Structural Database and the Protein Data Bank. Rotation along the N-C bond in the region of the amide group was found to be the reason for two relatively stable molecular conformations, an extended and a folded one. The role of various types of intermolecular interactions in stabilization of the particular molecular conformation was studied in terms of (i) the likelihood of H-bond formation, and (ii) their contribution to the Voronoi molecular surface. It is shown that experimentally observed hydrogen bonds are in accord with the likelihood of their formation. The number of H-bonds in ligand-receptor complexes surpasses that in imatinib salts due to the large number of donors and acceptors of H-bonding within the binding pocket of tyrosine kinases. Contribution of hydrophilic intermolecular interactions to the Voronoi molecular surface is similar for both conformations, while π...π stacking is more typical for the folded conformation of imatinib. Full article
(This article belongs to the Special Issue Conformations and Physicochemical Properties of Biological Ligands in Various Environments)
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11 pages, 1541 KiB  
Article
Theoretical Prediction of Dual-Potency Anti-Tumor Agents: Combination of Oxoplatin with Other FDA-Approved Oncology Drugs
by José Pedro Cerón-Carrasco
Int. J. Mol. Sci. 2020, 21(13), 4741; https://doi.org/10.3390/ijms21134741 - 03 Jul 2020
Cited by 8 | Viewed by 2387
Abstract
Although Pt(II)-based drugs are widely used to treat cancer, very few molecules have been approved for routine use in chemotherapy due to their side-effects on healthy tissues. A new approach to reducing the toxicity of these drugs is generating a prodrug by increasing [...] Read more.
Although Pt(II)-based drugs are widely used to treat cancer, very few molecules have been approved for routine use in chemotherapy due to their side-effects on healthy tissues. A new approach to reducing the toxicity of these drugs is generating a prodrug by increasing the oxidation state of the metallic center to Pt(IV), a less reactive form that is only activated once it enters a cell. We used theoretical tools to combine the parent Pt(IV) prodrug, oxoplatin, with the most recent FDA-approved anti-cancer drug set published by the National Institute of Health (NIH). The only prerequisite imposed for the latter was the presence of one carboxylic group in the structure, a chemical feature that ensures a link to the coordination sphere via a simple esterification procedure. Our calculations led to a series of bifunctional prodrugs ranked according to their relative stabilities and activation profiles. Of all the designed molecules, the combination of oxoplatin with aminolevulinic acid as the bioactive ligand emerged as the most promising strategy by which to design enhanced dual-potency oncology drugs. Full article
(This article belongs to the Special Issue Conformations and Physicochemical Properties of Biological Ligands in Various Environments)
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8 pages, 1922 KiB  
Article
Weak Interaction of the Antimetabolite Drug Methotrexate with a Cavitand Derivative
by Zsolt Preisz, Zoltán Nagymihály, Beáta Lemli, László Kollár and Sándor Kunsági-Máté
Int. J. Mol. Sci. 2020, 21(12), 4345; https://doi.org/10.3390/ijms21124345 - 18 Jun 2020
Cited by 5 | Viewed by 2188
Abstract
Formation of inclusion complexes involving a cavitand derivative (as host) and an antimetabolite drug, methotrexate (as guest) was investigated by photoluminescence measurements in dimethyl sulfoxide solvent. Molecular modeling performed in gas phase reflects that, due to the structural reasons, the cavitand can include [...] Read more.
Formation of inclusion complexes involving a cavitand derivative (as host) and an antimetabolite drug, methotrexate (as guest) was investigated by photoluminescence measurements in dimethyl sulfoxide solvent. Molecular modeling performed in gas phase reflects that, due to the structural reasons, the cavitand can include the methotrexate in two forms: either by its opened structure with free androsta-4-en-3-one-17α-ethinyl arms or by the closed form when all the androsta-4-en-3-one-17α-ethinyl arms play role in the complex formation. Experiments reflect enthalpy driven complex formation in higher temperature range while at lower temperature the complexes are stabilized by the entropy gain. Full article
(This article belongs to the Special Issue Conformations and Physicochemical Properties of Biological Ligands in Various Environments)
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Review

Jump to: Editorial, Research

23 pages, 3503 KiB  
Review
Two Decades of 4D-QSAR: A Dying Art or Staging a Comeback?
by Andrzej Bak
Int. J. Mol. Sci. 2021, 22(10), 5212; https://doi.org/10.3390/ijms22105212 - 14 May 2021
Cited by 16 | Viewed by 3447
Abstract
A key question confronting computational chemists concerns the preferable ligand geometry that fits complementarily into the receptor pocket. Typically, the postulated ‘bioactive’ 3D ligand conformation is constructed as a ‘sophisticated guess’ (unnecessarily geometry-optimized) mirroring the pharmacophore hypothesis—sometimes based on an erroneous prerequisite. Hence, [...] Read more.
A key question confronting computational chemists concerns the preferable ligand geometry that fits complementarily into the receptor pocket. Typically, the postulated ‘bioactive’ 3D ligand conformation is constructed as a ‘sophisticated guess’ (unnecessarily geometry-optimized) mirroring the pharmacophore hypothesis—sometimes based on an erroneous prerequisite. Hence, 4D-QSAR scheme and its ‘dialects’ have been practically implemented as higher level of model abstraction that allows the examination of the multiple molecular conformation, orientation and protonation representation, respectively. Nearly a quarter of a century has passed since the eminent work of Hopfinger appeared on the stage; therefore the natural question occurs whether 4D-QSAR approach is still appealing to the scientific community? With no intention to be comprehensive, a review of the current state of art in the field of receptor-independent (RI) and receptor-dependent (RD) 4D-QSAR methodology is provided with a brief examination of the ‘mainstream’ algorithms. In fact, a myriad of 4D-QSAR methods have been implemented and applied practically for a diverse range of molecules. It seems that, 4D-QSAR approach has been experiencing a promising renaissance of interests that might be fuelled by the rising power of the graphics processing unit (GPU) clusters applied to full-atom MD-based simulations of the protein-ligand complexes. Full article
(This article belongs to the Special Issue Conformations and Physicochemical Properties of Biological Ligands in Various Environments)
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26 pages, 4081 KiB  
Review
Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics
by Tomislav Jednačak, Ivana Mikulandra and Predrag Novak
Int. J. Mol. Sci. 2020, 21(20), 7799; https://doi.org/10.3390/ijms21207799 - 21 Oct 2020
Cited by 13 | Viewed by 4991
Abstract
Macrolide antibiotics are macrocyclic compounds that are clinically used and prescribed for the treatment of upper and lower respiratory tract infections. They inhibit the synthesis of bacterial proteins by reversible binding to the 23S rRNA at or near the peptidyl transferase center. However, [...] Read more.
Macrolide antibiotics are macrocyclic compounds that are clinically used and prescribed for the treatment of upper and lower respiratory tract infections. They inhibit the synthesis of bacterial proteins by reversible binding to the 23S rRNA at or near the peptidyl transferase center. However, their excellent antibacterial profile was largely compromised by the emergence of bacterial resistance. Today, fighting resistance to antibiotics is one of the greatest challenges in medicinal chemistry. Considering various physicochemical properties of macrolides, understanding their structure and interactions with macromolecular targets is crucial for the design of new antibiotics efficient against resistant pathogens. The solid-state structures of some macrolide-ribosome complexes have recently been solved, throwing new light on the macrolide binding mechanisms. On the other hand, a combination of NMR spectroscopy and molecular modeling calculations can be applied to study free and bound conformations in solution. In this article, a description of advanced physicochemical methods for elucidating the structure and interactions of macrolide antibiotics in solid state and solution will be provided, and their principal advantages and drawbacks will be discussed. Full article
(This article belongs to the Special Issue Conformations and Physicochemical Properties of Biological Ligands in Various Environments)
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