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Molecular Approaches to Drug Discovery and Development

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

Deadline for manuscript submissions: 31 December 2024 | Viewed by 4017

Special Issue Editor


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Guest Editor
Department of Chemistry, University of Patras, 26504 Patras, Greece
Interests: organic synthesis; medicinal chemistry; drug delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug discovery involves many different stages, such as target identification and validation, hit identification, hit-to-lead optimization, and the identification of a candidate for further development. Drug development, on the other hand, includes the optimization of chemical synthesis and drug formulation, preclinical studies, and, eventually, market approval. It is evident that drug development, from the discovery of a promising target to the creation of usable medication, is a costly, long process. It has also become clear that the need for faster drug development requires interdisciplinary cooperation within academia, as well as increased collaboration between industry and academia with a common objective of constantly providing quality medicines.

Organic chemistry has had a major impact on drug discovery by providing simple and efficient, low-cost synthetic pathways, novel methodologies, and reaction mechanisms for the synthesis of new candidate molecules. In addition to drug discovery, organic chemistry is greatly involved in drug development and optimization. The rapid development of biotechnological drugs and synthetic drug delivery systems has re-enforced the role of organic chemistry, as there is a clear need for the development of targeting drugs, nano-drugs, and synthetic drug delivery systems in a controllable, reproducible, and well-defined manner.

This Special Issue will collect the contributions of various types of molecular approaches to drug discovery and development, i.e., the synthesis of potential bioactive molecules and drugs and drug derivatives, including targeted drugs and synthetic novel-type drug delivery systems (DDS). The following categories will form part of this Special Issue: liquid- and solid-phase synthesis methods for the development of bioactive molecules and drugs of any type (small molecules, macromolecules, peptides and their derivatives); methods used to extend drugs’ self-lives (e.g., lipidation, pegylation, chemical/structural modifications, cyclization, etc.); methods used to enhance targeting ability; the development of targeted drug delivery systems; synthetic approaches to the latest oligonucleotide-mediated gene silencing concept. Molecular mechanisms of innovating synthetic approaches/problem solving also form part of this Special Issue. The development of innovative synthetic nano-drugs and vesicular drug delivery systems (DDS) that allow slow release and extend the drugs half-life (e.g., liposomes, nanoparticles, etc.) will also be considered for publication if the applied molecular approaches/chemistries used, either to the DDS or the drug itself, influence the fate of the drug after administration (e.g., synthetic modifications/functionalization, targeted drug-delivery systems, etc.). Initial biological and pharmacological evaluation (including preclinical evaluation) of the suggested compounds/systems is also welcome.

Dr. Spyridon Mourtas
Guest Editor

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Keywords

  • molecular approaches
  • molecular mechanisms
  • molecular rearrangements
  • liquid- and solid-phase synthesis
  • organic molecules
  • peptides
  • drugs
  • chemical modifications
  • organic synthesis
  • nano-drugs
  • synthetic drug delivery systems
  • targeting

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Published Papers (3 papers)

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Research

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17 pages, 3890 KiB  
Article
Visible-Light-Induced Diselenide-Crosslinked Polymeric Micelles for ROS-Triggered Drug Delivery
by Xinfeng Cheng, Huixian Li, Xiaomeng Sun, Tianxu Xu, Zhenzhen Guo, Xianchao Du, Shuai Li, Xuyang Li, Xiaojing Xing and Dongfang Qiu
Molecules 2024, 29(16), 3970; https://doi.org/10.3390/molecules29163970 - 22 Aug 2024
Viewed by 481
Abstract
To synthesize an effective and versatile nano-platform serving as a promising carrier for controlled drug delivery, visible-light-induced diselenide-crosslinked polyurethane micelles were designed and prepared for ROS-triggered on-demand doxorubicin (DOX) release. A rationally designed amphiphilic block copolymer, poly(ethylene glycol)-b-poly(diselenolane diol-co-isophorone diisocyanate)-b [...] Read more.
To synthesize an effective and versatile nano-platform serving as a promising carrier for controlled drug delivery, visible-light-induced diselenide-crosslinked polyurethane micelles were designed and prepared for ROS-triggered on-demand doxorubicin (DOX) release. A rationally designed amphiphilic block copolymer, poly(ethylene glycol)-b-poly(diselenolane diol-co-isophorone diisocyanate)-b-poly(ethylene glycol) (PEG-b-PUSe-b-PEG), which incorporates dangling diselenolane groups within the hydrophobic PU segments, was initially synthesized through the polycondensation reaction. In aqueous media, this type of amphiphilic block copolymer can self-assemble into micellar aggregates and encapsulate DOX within the micellar core, forming DOX-loaded micelles that are subsequently in situ core-crosslinked by diselenides via a visible-light-triggered metathesis reaction of Se-Se bonds. Compared with the non-crosslinked micelles (NCLMs), the as-prepared diselenide-crosslinked micelles (CLMs) exhibited a smaller particle size and improved colloidal stability. In vitro release studies have demonstrated suppressed drug release behavior for CLMs in physiological conditions, as compared to the NCLMs, whereas a burst release of DOX occurred upon exposure to an oxidation environment. Moreover, MTT assay results have revealed that the crosslinked polyurethane micelles displayed no significant cytotoxicity towards HeLa cells. Cellular uptake analyses have suggested the effective internalization of DOX-loaded crosslinked micelles and DOX release within cancer cells. These findings suggest that this kind of ROS-triggered reversibly crosslinked polyurethane micelles hold significant potential as a ROS-responsive drug delivery system. Full article
(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)
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20 pages, 2123 KiB  
Article
Synthesis of α,ω-bis-Mercaptoacyl Poly(alkyl oxide)s and Development of Thioether Cross-Linked Liposome Scaffolds for Sustained Release of Drugs
by Spyridon Mourtas, Georgios Kourmoulakis, Stavros Kremezis, Pavlos Klepetsanis and Sophia G. Antimisiaris
Molecules 2024, 29(6), 1312; https://doi.org/10.3390/molecules29061312 - 15 Mar 2024
Viewed by 962
Abstract
With the aim to develop novel scaffolds for the sustained release of drugs, we initially developed an easy approach for the synthesis of α,ω-homobifunctional mercaptoacyl poly(alkyl oxide)s. This was based on the esterification of the terminal hydroxyl groups of poly(alkyl oxide)s with suitably [...] Read more.
With the aim to develop novel scaffolds for the sustained release of drugs, we initially developed an easy approach for the synthesis of α,ω-homobifunctional mercaptoacyl poly(alkyl oxide)s. This was based on the esterification of the terminal hydroxyl groups of poly(alkyl oxide)s with suitably S-4-methoxytrityl (Mmt)-protected mercapto acids, followed by the removal of the acid labile S-Mmt group. This method allowed for the efficient synthesis of the title compounds in high yield and purity, which were further used in the development of a thioether cross-linked liposome scaffold, by thia–Michael reaction of the terminal thiol groups with pre-formed nano-sized liposomes bearing maleimide groups on their surface. The reaction process was followed by 1H-NMR, using a Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion NMR experiment (1H-NMR CPMG), which allowed for real-time monitoring and optimization of the reaction process. The thioether cross-linked liposomal scaffold that was synthesized was proven to preserve the nano-sized characteristics of the initial liposomes and allowed for the sustained release of calcein (which was used as a hydrophilic dye and a hydrophilic drug model), providing evidence for the efficient synthesis of a novel drug release scaffold consisting of nanoliposome building blocks. Full article
(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)
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Review

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18 pages, 4988 KiB  
Review
Recent Advances in Amphipathic Peptidomimetics as Antimicrobial Agents to Combat Drug Resistance
by Ma Su and Yongxiang Su
Molecules 2024, 29(11), 2492; https://doi.org/10.3390/molecules29112492 - 24 May 2024
Cited by 1 | Viewed by 814
Abstract
The development of antimicrobial drugs with novel structures and clear mechanisms of action that are active against drug-resistant bacteria has become an urgent need of safeguarding human health due to the rise of bacterial drug resistance. The discovery of AMPs and the development [...] Read more.
The development of antimicrobial drugs with novel structures and clear mechanisms of action that are active against drug-resistant bacteria has become an urgent need of safeguarding human health due to the rise of bacterial drug resistance. The discovery of AMPs and the development of amphipathic peptidomimetics have lay the foundation for novel antimicrobial agents to combat drug resistance due to their overall strong antimicrobial activities and unique membrane-active mechanisms. To break the limitation of AMPs, researchers have invested in great endeavors through various approaches in the past years. This review summarized the recent advances including the development of antibacterial small molecule peptidomimetics and peptide-mimic cationic oligomers/polymers, as well as mechanism-of-action studies. As this exciting interdisciplinary field is continuously expanding and growing, we hope this review will benefit researchers in the rational design of novel antimicrobial peptidomimetics in the future. Full article
(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)
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