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Recent Advances in Drug Discovery
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Recent Advances in Drug Discovery

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 October 2023) | Viewed by 11642

Special Issue Editors

Prof. Dr. Patricia Fernandes

E-Mail Website
Guest Editor
Laboratory of Pain and Inflammation, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Interests: pharmacology of pain; inflammation; cancer; natural products
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Carlos Alberto Manssour Fraga

E-Mail Website
Guest Editor
1. Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
2. Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
Interests: medicinal chemistry; drug design and discovery; multitarget drugs for neurodegenerative diseases; use of privileged structures to design new epigenetic drug candidates; discovery of new kinase inhibitors for chronic inflammatory diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The discovery of new drugs is a continuous objective of researchers in academia and pharmaceutical companies. The processes of drug discovery provide an important source of new drug prototypes for future drug development, which may result in new medicines. While numerous developments have be seen, including a reduction in the timescales, complexity, and cost and enhancement of the the precision, there is still a long way to go. These facts still represent challenges to modern drug discovery. The discovery of new drugs is hard because it is very rare to discover a molecule—either natural or artificial—that is a hit against a protein target implicated in a disease. This difficult may occur due to a variety of reasons, including toxicity, efficacy, physicochemical properties, bioavailability, or inadequate drug performance. In view of these, the continuous search for new compounds with high potency and lesser side effects is a permanent objective.

This Special Issue, “Recent Advances in Drug Discovery”, will focus on synthesis and/or biological effects of new compounds designed using medicinal chemistry approaches looking for improving activities against worldwide diseases, including, but not limited to, neglect diseases, chronic inflammatory diseases, cancer, tropical diseases (malaria, leishmaniosis, dengue, zika), and neurological diseases.

We look forward to your contribution to this exciting Special Issue.

Dr. Patricia Dias Fernandes
Prof. Dr. Carlos Alberto Manssour Fraga
Guest Editors

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

  • medicinal chemistry
  • inflammation
  • cancer
  • pain
  • drug design and discovery
  • chronic inflammatory diseases
  • neglected diseases
  • drug screening

Published Papers (5 papers)

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Research

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12 pages, 2194 KiB  
Article
Screening and Analysis of Possible Drugs Binding to PDGFRα: A Molecular Modeling Study
by Matteo Mozzicafreddo, Devis Benfaremo, Chiara Paolini, Silvia Agarbati, Silvia Svegliati Baroni and Gianluca Moroncini
Int. J. Mol. Sci. 2023, 24(11), 9623; https://doi.org/10.3390/ijms24119623 - 01 Jun 2023
Cited by 3 | Viewed by 1735
Abstract
The platelet-derived growth factor receptor (PDGFR) is a membrane tyrosine kinase receptor involved in several metabolic pathways, not only physiological but also pathological, as in tumor progression, immune-mediated diseases, and viral diseases. Considering this macromolecule as a druggable target for modulation/inhibition of these [...] Read more.
The platelet-derived growth factor receptor (PDGFR) is a membrane tyrosine kinase receptor involved in several metabolic pathways, not only physiological but also pathological, as in tumor progression, immune-mediated diseases, and viral diseases. Considering this macromolecule as a druggable target for modulation/inhibition of these conditions, the aim of this work was to find new ligands or new information to design novel effective drugs. We performed an initial interaction screening with the human intracellular PDGFRα of about 7200 drugs and natural compounds contained in 5 independent databases/libraries implemented in the MTiOpenScreen web server. After the selection of 27 compounds, a structural analysis of the obtained complexes was performed. Three-dimensional quantitative structure–activity relationship (3D-QSAR) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were also performed to understand the physicochemical properties of identified compounds to increase affinity and selectivity for PDGFRα. Among these 27 compounds, the drugs Bafetinib, Radotinib, Flumatinib, and Imatinib showed higher affinity for this tyrosine kinase receptor, lying in the nanomolar order, while the natural products included in this group, such as curcumin, luteolin, and epigallocatechin gallate (EGCG), showed sub-micromolar affinities. Although experimental studies are mandatory to fully understand the mechanisms behind PDGFRα inhibitors, the structural information obtained through this study could provide useful insight into the future development of more effective and targeted treatments for PDGFRα-related diseases, such as cancer and fibrosis. Full article
(This article belongs to the Special Issue Recent Advances in Drug Discovery)
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14 pages, 4642 KiB  
Article
Desorption Kinetics Evaluation for the Development of Validated Desorption Electrospray Ionization-Mass Spectrometric Assays for Drug Quantification in Tissue Sections
by Margaux Fresnais, Siwen Liang, Deniz Seven, Nevena Prodanovic, Julia Sundheimer, Walter E. Haefeli, Jürgen Burhenne and Rémi Longuespée
Int. J. Mol. Sci. 2023, 24(10), 8469; https://doi.org/10.3390/ijms24108469 - 09 May 2023
Viewed by 2731
Abstract
The development of desorption/ionization (DI) mass spectrometric (MS) assays for drug quantification in tissue sections and their validation according to regulatory guidelines would enable their universalization for applications in (clinical) pharmacology. Recently, new enhancements in desorption electrospray ionization (DESI) have highlighted the reliability [...] Read more.
The development of desorption/ionization (DI) mass spectrometric (MS) assays for drug quantification in tissue sections and their validation according to regulatory guidelines would enable their universalization for applications in (clinical) pharmacology. Recently, new enhancements in desorption electrospray ionization (DESI) have highlighted the reliability of this ion source for the development of targeted quantification methods that meet requirements for method validation. However, it is necessary to consider subtle parameters leading to the success of such method developments, such as the morphology of desorption spots, the analytical time, and sample surface, to cite but a few. Here, we provide additional experimental data highlighting an additional important parameter, based on the unique advantage of DESI-MS on continuous extraction during analysis. We demonstrate that considering desorption kinetics during DESI analyses would largely help (i) reducing analytical time during profiling analyses, (ii) verifying solvent-based drug extraction using the selected sample preparation method for profiling and imaging modes, and (iii) predicting the feasibility of imaging assays using samples in a given expected concentration range of the targeted drug. These observations will likely serve as precious guidance for the development of validated DESI-profiling and imaging methods in the future. Full article
(This article belongs to the Special Issue Recent Advances in Drug Discovery)
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Review

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14 pages, 895 KiB  
Review
Liposome-Based Carriers for CRISPR Genome Editing
by Xing Yin, Romain Harmancey, David D. McPherson, Hyunggun Kim and Shao-Ling Huang
Int. J. Mol. Sci. 2023, 24(16), 12844; https://doi.org/10.3390/ijms241612844 - 16 Aug 2023
Cited by 2 | Viewed by 1716
Abstract
The CRISPR-based genome editing technology, known as clustered regularly interspaced short palindromic repeats (CRISPR), has sparked renewed interest in gene therapy. This interest is accompanied by the development of single-guide RNAs (sgRNAs), which enable the introduction of desired genetic modifications at the targeted [...] Read more.
The CRISPR-based genome editing technology, known as clustered regularly interspaced short palindromic repeats (CRISPR), has sparked renewed interest in gene therapy. This interest is accompanied by the development of single-guide RNAs (sgRNAs), which enable the introduction of desired genetic modifications at the targeted site when used alongside the CRISPR components. However, the efficient delivery of CRISPR/Cas remains a challenge. Successful gene editing relies on the development of a delivery strategy that can effectively deliver the CRISPR cargo to the target site. To overcome this obstacle, researchers have extensively explored non-viral, viral, and physical methods for targeted delivery of CRISPR/Cas9 and a guide RNA (gRNA) into cells and tissues. Among those methods, liposomes offer a promising approach to enhance the delivery of CRISPR/Cas and gRNA. Liposomes facilitate endosomal escape and leverage various stimuli such as light, pH, ultrasound, and environmental cues to provide both spatial and temporal control of cargo release. Thus, the combination of the CRISPR-based system with liposome delivery technology enables precise and efficient genetic modifications in cells and tissues. This approach has numerous applications in basic research, biotechnology, and therapeutic interventions. For instance, it can be employed to correct genetic mutations associated with inherited diseases and other disorders or to modify immune cells to enhance their disease-fighting capabilities. In summary, liposome-based CRISPR genome editing provides a valuable tool for achieving precise and efficient genetic modifications. This review discusses future directions and opportunities to further advance this rapidly evolving field. Full article
(This article belongs to the Special Issue Recent Advances in Drug Discovery)
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25 pages, 2821 KiB  
Review
Expected and Unexpected Effects of Pharmacological Antioxidants
by Irina Tyuryaeva and Olga Lyublinskaya
Int. J. Mol. Sci. 2023, 24(11), 9303; https://doi.org/10.3390/ijms24119303 - 26 May 2023
Cited by 5 | Viewed by 1841
Abstract
In this review, we have collected the existing data on the bioactivity of antioxidants (N-acetylcysteine, polyphenols, vitamin C) which are traditionally used in experimental biology and, in some cases, in the clinic. Presented data show that, despite the capacity of these substances to [...] Read more.
In this review, we have collected the existing data on the bioactivity of antioxidants (N-acetylcysteine, polyphenols, vitamin C) which are traditionally used in experimental biology and, in some cases, in the clinic. Presented data show that, despite the capacity of these substances to scavenge peroxides and free radicals in cell-free systems, their ability to exhibit these properties in vivo, upon pharmacological supplementation, has not been confirmed so far. Their cytoprotective activity is explained mainly by the ability not to suppress, but to activate multiple redox pathways, which causes biphasic hormetic responses and highly pleiotropic effects in cells. N-acetylcysteine, polyphenols, and vitamin C affect redox homeostasis by generating low-molecular-weight redox-active compounds (H2O2 or H2S), known for their ability to stimulate cellular endogenous antioxidant defense and promote cytoprotection at low concentrations but exert deleterious effects at high concentrations. Moreover, the activity of antioxidants strongly depends on the biological context and mode of their application. We show here that considering the biphasic and context-dependent response of cells on the pleiotropic action of antioxidants can help explain many of the conflicting results obtained in basic and applied research and build a more logical strategy for their use. Full article
(This article belongs to the Special Issue Recent Advances in Drug Discovery)
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19 pages, 2307 KiB  
Review
Arylcyclohexylamine Derivatives: Pharmacokinetic, Pharmacodynamic, Clinical and Forensic Aspects
by Romain Pelletier, Brendan Le Daré, Diane Le Bouëdec, Angéline Kernalléguen, Pierre-Jean Ferron, Isabelle Morel and Thomas Gicquel
Int. J. Mol. Sci. 2022, 23(24), 15574; https://doi.org/10.3390/ijms232415574 - 08 Dec 2022
Cited by 6 | Viewed by 3073
Abstract
Since the 2000s, an increasing number of new psychoactive substances (NPS) have appeared on the drug market. Arylcyclohexylamine (ACH) compounds such as ketamine, phencyclidine and eticyclidine derivatives are of particular concern, given their rapidly increasing use and the absence of detailed toxicity data. [...] Read more.
Since the 2000s, an increasing number of new psychoactive substances (NPS) have appeared on the drug market. Arylcyclohexylamine (ACH) compounds such as ketamine, phencyclidine and eticyclidine derivatives are of particular concern, given their rapidly increasing use and the absence of detailed toxicity data. First used mainly for their pharmacological properties in anesthesia, their recreational use is increasing. ACH derivatives have an antagonistic activity against the N-methyl-D-aspartate receptor, which leads to dissociative effects (dissociation of body and mind). Synthetic ketamine derivatives produced in Asia are now arriving in Europe, where most are not listed as narcotics and are, thus, legal. These structural derivatives have pharmacokinetic and pharmacodynamic properties that are sometimes very different from ketamine. Here, we describe the pharmacology, epidemiology, chemistry and metabolism of ACH derivatives, and we review the case reports on intoxication. Full article
(This article belongs to the Special Issue Recent Advances in Drug Discovery)
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