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Techniques and Strategies in Drug Design and Discovery, 2nd Edition
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Techniques and Strategies in Drug Design and Discovery, 2nd Edition

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

Deadline for manuscript submissions: 20 September 2024 | Viewed by 2742

Special Issue Editor

Prof. Dr. George Mihai Nitulescu

E-Mail Website
Guest Editor
Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 6 Traian Vuia Street, 020956 Bucharest, Romania
Interests: the design and synthesis of new anticancer agents; the design and synthesis of new antimicrobial compounds; studies and structural analysis; the isolation and analysis of natural compounds with anticancer effects; computer-assisted drug design studies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug discovery is a very complex and difficult process that involves finding and developing novel therapeutic entities. In recent years, the methodology behind drug discovery has rapidly evolved and comprises a plethora of paradigms and techniques, but there remains no perfect algorithm for guaranteed success. Despite considerable research, fortunate discoveries and the incredible intuition, inspiration, and creativity of researchers still play a vital role in the field of drug discovery, which remains popular among many scientists. Novel approaches and innovations are needed to address the dominant challenge of cost efficiency. In light of this challenge, novel approaches and innovations are imperative. To address this pressing issue, we are pleased to announce the continuation of our previous Special Issue, which is dedicated to serving as a comprehensive platform for researchers working in this field. This Special Issue provides an inclusive space for presenting recent efforts aimed at enhancing current methodologies and discovering new molecular entities. We welcome innovative research contributions, as well as insightful reviews of existing practices, in all facets of drug discovery and drug development.

In the first edition, eight papers were published; we sincerely welcome you to read these papers and contribute to this 2nd edition. We believe that through collaborative efforts and the exchange of knowledge in this Special Issue, we can drive significant advancements in drug discovery and ultimately improve global healthcare outcomes.

Prof. Dr. George Mihai Nitulescu
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

  • drug discovery
  • drug development
  • target identification
  • computational drug design
  • structure-based drug design
  • ligand-based drug design

Published Papers (4 papers)

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Research

24 pages, 1060 KiB  
Article
Studies on the Thermal Decomposition Course of Nitrogen-Rich Heterocyclic Esters as Potential Drug Candidates and Evaluation of Their Thermal Stability and Properties
by Marta Worzakowska, Krzysztof Sztanke and Małgorzata Sztanke
Int. J. Mol. Sci. 2024, 25(9), 4768; https://doi.org/10.3390/ijms25094768 (registering DOI) - 27 Apr 2024
Viewed by 193
Abstract
Drug candidates must undergo thermal evaluation as early as possible in the preclinical phase of drug development because undesirable changes in their structure and physicochemical properties may result in decreased pharmacological activity or enhanced toxicity. Hence, the detailed evaluation of nitrogen-rich heterocyclic esters [...] Read more.
Drug candidates must undergo thermal evaluation as early as possible in the preclinical phase of drug development because undesirable changes in their structure and physicochemical properties may result in decreased pharmacological activity or enhanced toxicity. Hence, the detailed evaluation of nitrogen-rich heterocyclic esters as potential drug candidates, i.e., imidazolidinoannelated triazinylformic acid ethyl esters 1–3 (where R1 = 4–CH3 or 4–OCH3 or 4–Cl, and R2 = –COOC2H5) and imidazolidinoannelated triazinylacetic acid methyl esters 4–6 (where R1 = 4–CH3 or 4–OCH3 or 4–Cl, and R2 = –CH2COOCH3)—in terms of their melting points, melting enthalpy values, thermal stabilities, pyrolysis, and oxidative decomposition course—has been carried out, using the simultaneous thermal analysis methods (TG/DTG/DSC) coupled with spectroscopic techniques (FTIR and QMS). It was found that the melting process (documented as one sharp peak related to the solid–liquid phase transition) of the investigated esters proceeded without their thermal decomposition. It was confirmed that the melting points of the tested compounds increased in relation to R1 and R2 as follows: 2 (R1 = 4–OCH3; R2 = –COOC2H5) < 6 (R1 = 4–Cl; R2 = –CH2COOCH3) < 5 (R1 = 4–OCH3; R2 = –CH2COOCH3) < 3 (R1 = 4–Cl; R2 = –COOC2H5) < 1 (R1 = 4–CH3; R2 = –COOC2H5) < 4 (R1 = 4–CH3; R2 = –CH2COOCH3). All polynitrogenated heterocyclic esters proved to be thermally stable up to 250 °C in inert and oxidising conditions, although 1–3 were characterised by higher thermal stability compared to 4–6. The results confirmed that both the pyrolysis and the oxidative decomposition of heterocyclic ethyl formates/methyl acetates with para-substitutions at the phenyl moiety proceed according to the radical mechanism. In inert conditions, the pyrolysis process of the studied molecules occurred with the homolytic breaking of the C–C, C–N, and C–O bonds. This led to the emission of alcohol (ethanol in the case of 1–3 or methanol in the case of 4–6), NH3, HCN, HNCO, aldehydes, CO2, CH4, HCl, aromatics, and H2O. In turn, in the presence of air, cleavage of the C–C, C–N, and C–O bonds connected with some oxidation and combustion processes took place. This led to the emission of the corresponding alcohol depending on the analysed class of heterocyclic esters, NH3, HCN, HNCO, aldehydes, N2, NO/NO2, CO, CO2, HCl, aromatics, and H2O. Additionally, after some biological tests, it was proven that all nitrogen-rich heterocyclic esters—as potential drug candidates—are safe for erythrocytes, and some of them are able to protect red blood cells from oxidative stress-induced damage. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery, 2nd Edition)
10 pages, 2252 KiB  
Article
Mechanism of Action of Antitumor Au(I) N-Heterocyclic Carbene Complexes: A Computational Insight on the Targeting of TrxR Selenocysteine
by Iogann Tolbatov, Paolo Umari and Alessandro Marrone
Int. J. Mol. Sci. 2024, 25(5), 2625; https://doi.org/10.3390/ijms25052625 - 23 Feb 2024
Viewed by 481
Abstract
The targeting of human thioredoxin reductase is widely recognized to be crucially involved in the anticancer properties of several metallodrugs, including Au(I) complexes. In this study, the mechanism of reaction between a set of five N-heterocyclic carbene Au(I) complexes and models of the [...] Read more.
The targeting of human thioredoxin reductase is widely recognized to be crucially involved in the anticancer properties of several metallodrugs, including Au(I) complexes. In this study, the mechanism of reaction between a set of five N-heterocyclic carbene Au(I) complexes and models of the active Sec residue in human thioredoxin reductase was investigated by means of density functional theory approaches. The study was specifically addressed to the kinetics and thermodynamics of the tiled process by aiming at elucidating and explaining the differential inhibitory potency in this set of analogous Au(I) bis-carbene complexes. While the calculated free energy profile showed a substantially similar reactivity, we found that the binding of these Au(I) bis-carbene at the active CysSec dyad in the TrxR enzyme could be subjected to steric and orientational restraints, underlining both the approach of the bis-carbene scaffold and the attack of the selenol group at the metal center. A new and detailed mechanistic insight to the anticancer activity of these Au(I) organometallic complexes was thus provided by consolidating the TrxR targeting paradigm. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery, 2nd Edition)
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17 pages, 5587 KiB  
Article
Application of Simultaneous and Coupled Thermal Analysis Techniques in Studies on the Melting Process, Course of Pyrolysis and Oxidative Decomposition of Fused Triazinylacetohydrazides
by Marta Worzakowska, Krzysztof Sztanke and Małgorzata Sztanke
Int. J. Mol. Sci. 2024, 25(2), 813; https://doi.org/10.3390/ijms25020813 - 09 Jan 2024
Cited by 1 | Viewed by 615
Abstract
The effect of the structure of promising antioxidant agents with prospective medical use, i.e., unsubstituted and para-substituted annelated triazinylacetic acid hydrazides, on their melting points, thermal stabilities, pyrolysis and oxidative decomposition stages and the type of volatiles emitted under heating with the [...] Read more.
The effect of the structure of promising antioxidant agents with prospective medical use, i.e., unsubstituted and para-substituted annelated triazinylacetic acid hydrazides, on their melting points, thermal stabilities, pyrolysis and oxidative decomposition stages and the type of volatiles emitted under heating with the use of DSC and TG/DTG/FTIR/QMS methods was evaluated and discussed. The melting point of the investigated compounds increased with an enhanced number of electrons (directly correlated with their molecular weight). Melting enthalpy values were determined and presented for all the studied compounds. The pyrolysis and oxidative decomposition processes of the analysed molecules consisted of several poorly separated stages, which indicated a multi-step course of the decomposition reactions. It was found that the thermal stability of the tested compounds depended on the type of substituent at the para position of the phenyl moiety or its absence. In both atmospheres used (air and helium), the thermal stability increased in relation to R as follows: -CH3 ≤ -OCH3 < -H < -OC2H5. In an inert atmosphere, it was higher by approx. 8–18 °C than in an oxidative atmosphere. The pyrolysis was connected with the emission of NH3, HCN, HNCO, HCONH2, HCHO, CO2, CO and H2O in the case of all the tested compounds, regardless of the substituent attached. In the case of the derivative containing the para-CH3 group, para-toluidine was an additional emitted aromatic product. In turn, emissions of aniline and alcohol (methanol or ethanol) for compounds with the para-OCH3 and para-OC2H5 groups, respectively, were confirmed. In oxidative conditions, the release of NH3, NO, HCN, HNCO, HCONH2, CO2, H2O and cyanogen (for all the compounds) and para-toluidine (for the para-CH3 derivative), aniline (for para-OCH3, para-OC2H5 and unsubstituted derivatives) and acetaldehyde (for the para-OC2H5 derivative) were clearly observed. No alcohol emissions were recorded for either compound containing the para-OCH3- or para-OC2H5-substitututed phenyl ring. These results confirmed that the pyrolysis and oxidative decomposition of the investigated annelated triazinylacetohydrazides occurred according to the radical mechanism. Moreover, in the presence of oxygen, the reactions of volatiles and residues with oxygen (oxidation) and the combustion process additionally proceeded. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery, 2nd Edition)
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18 pages, 5532 KiB  
Article
Exploiting the Features of Short Peptides to Recognize Specific Cell Surface Markers
by Michela Buonocore, Manuela Grimaldi, Angelo Santoro, Verdiana Covelli, Carmen Marino, Enza Napolitano, Sara Novi, Mario Felice Tecce, Elena Ciaglia, Francesco Montella, Valentina Lopardo, Valeria Perugini, Matteo Santin and Anna Maria D’Ursi
Int. J. Mol. Sci. 2023, 24(21), 15610; https://doi.org/10.3390/ijms242115610 - 26 Oct 2023
Cited by 1 | Viewed by 954
Abstract
Antibodies are the macromolecules of choice to ensure specific recognition of biomarkers in biological assays. However, they present a range of shortfalls including a relatively high production cost and limited tissue penetration. Peptides are relatively small molecules able to reproduce sequences of highly [...] Read more.
Antibodies are the macromolecules of choice to ensure specific recognition of biomarkers in biological assays. However, they present a range of shortfalls including a relatively high production cost and limited tissue penetration. Peptides are relatively small molecules able to reproduce sequences of highly specific paratopes and, although they have less biospecificity than antibodies, they offer advantages like ease of synthesis, modifications of their amino acid sequences and tagging with fluorophores and other molecules required for detection. This work presents a strategy to design peptide sequences able to recognize the CD44 hyaluronic acid receptor present in the plasmalemma of a range of cells including human bone marrow stromal mesenchymal cells. The protocol of identification of the optimal amino acid sequence was based on the combination of rational design and in silico methodologies. This protocol led to the identification of two peptide sequences which were synthesized and tested on human bone marrow mesenchymal stromal cells (hBM-MSCs) for their ability to ensure specific binding to the CD44 receptor. Of the two peptides, one binds CD44 with sensitivity and selectivity, thus proving its potential to be used as a suitable alternative to this antibody in conventional immunostaining. In the context of regenerative medicine, the availability of this peptide could be harnessed to functionalize tissue engineering scaffolds to anchor stem cells as well as to be integrated into systems such as cell sorters to efficiently isolate MSCs from biological samples including various cell subpopulations. The data here reported can represent a model for developing peptide sequences able to recognize hBM-MSCs and other types of cells and for their integration in a range of biomedical applications. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery, 2nd Edition)
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