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Molecular Approaches to Drug Discovery and Development

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

Deadline for manuscript submissions: closed (28 February 2025) | Viewed by 11800

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Dr. Spyridon Mourtas

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Department of Chemistry, University of Patras, 26504 Patras, Greece
Interests: organic synthesis; medicinal chemistry; drug delivery
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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 (10 papers)

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Research

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15 pages, 5094 KiB

Open AccessArticle

Unraveling the Specific Recognition Between PD-L1 and Engineered CLP002 Functionalized Gold Nanostructures: MD Simulation Studies

by Micaela Giannetti, Marina Gobbo, Lucio Litti, Isabella Caligiuri, Flavio Rizzolio, Moreno Meneghetti, Claudia Mazzuca and Antonio Palleschi

Molecules 2025, 30(9), 2045; https://doi.org/10.3390/molecules30092045 - 4 May 2025

Viewed by 238

Abstract

PD-L1 (programmed cell death ligand-1) is a protein located on the surface of regulatory cells. It has an immunosuppressive role as it binds specifically to the protein programmed cell death-1 (PD-1), a checkpoint glycoprotein, present on the surface of immune cells such as T and B lymphocytes. Many tumor cells block the immune response by overexpressing PD-L1 on their surface; therefore, targeting PD-L1 represents a powerful strategy that allows tumor localization. To determine the presence of PD-L1 in cells, the use of ad hoc functionalized peptides that bind to PD-L1 can be exploited. One of them is the peptide CLP002 (Trp-His-Arg-Ser-Tyr-Tyr-Thr-Trp-Asn-Leu-Asn-Thr), which, bound to surface-enhanced Raman scattering (SERS) gold nanostructures via a suitable linker, was shown to be highly effective in recognizing MDA-MB-231 breast cancer cells and, importantly, this recognition can be measured by SERS experiments. To characterize, on a molecular scale, the interaction between PD-L1 and peptide functionalized nanostructures, we performed molecular dynamics (MDs) simulations, studying the features of peptide monolayers bound on gold surfaces in the absence and presence of PD-L1. The results obtained allow us to explain why the nature of the linker plays a fundamental role in the binding and why a peptide carrying the same amino acids as CPL002 but with a different sequence (scrambled) is much less active than CLP002. These results open the way to an in silico evaluation of the key parameters that regulate the binding of PD-L1 useful for cancer recognition. Full article

(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)

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15 pages, 1951 KiB

Open AccessArticle

Liposomes for Magnetic Resonance Image-Guided Drug Delivery; Lipid Chain Length Affects Drug Release and MRI Relaxivity

by Paul Cressey, Jacob C. Wilson, Maral Amrahli and Maya Thanou

Molecules 2025, 30(8), 1729; https://doi.org/10.3390/molecules30081729 - 11 Apr 2025

Viewed by 375

Abstract

Image-guided drug delivery is a method for tracking drug carriers for activation in specific lesions in the body. Image guidance uses the labelling of the drug or carrier and a clinically approved imaging modality. MRI (magnetic resonance image)-guided drug delivery has been considered for focused ultrasound tumour-targeted drug release. Liposomes are labelled for MRI tracking and the confirmation of drug delivery. In this study, we prepared two lipids conjugated to Gd-DOTA that confer MR imaging properties. Two lipid conjugates to DOTA, a C₁₈ (LCA-1) and a C₁₆ (LCA-2), were synthesised. The lipids were combined at different ratios within the lipid mix, and we investigated their effects on the liposome’s T_m using DSC (differential scanning calorimetry) and on relaxivity using NMR. The results show that when different combinations of LCA-1 and LCA-2 were introduced into the liposomes, their ratio affected both thermal drug release and relaxivity. As these lipids are part of the liposomal membrane, they confer tracking ability, and their effect on relaxivity due to thermal release could enable the confirmation of liposomal drug release using MRI at clinically relevant magnetic field strengths. Full article

(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)

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20 pages, 2510 KiB

Open AccessArticle

Development of Vancomycin, a Glycopeptide Antibiotic, in a Suitable Nanoform for Oral Delivery

by Ali A. Amer, Lewis Bingle, Cheng Shu Chaw and Amal Ali Elkordy

Molecules 2025, 30(7), 1624; https://doi.org/10.3390/molecules30071624 - 5 Apr 2025

Viewed by 588

Abstract

Bacterial infections caused by resistant strains have emerged as one of the most significant life-threatening challenges. Developing alternatives to conventional antibiotic formulations is crucial to overcoming these challenges. Vancomycin HCl (VCM) is a glycopeptide antibiotic used for Gram-positive bacterial infections that must be given intravenously for systemic infections since it cannot pass through the gut wall due to its chemical structure and characteristics. The aim of this research is to develop VCM in a niosomal nanoform to then be encapsulated in fast-disintegrating oral films for effective delivery to enhance the application of vancomycin-loaded niosomes for treating oral infections and to be used in dental treatments. The formulation of niosomes encapsulating VCM was conducted with various ratios of Span 40, Span 60, and cholesterol as well as Kolliphor RH40 and Kolliphor ELP as co-surfactants using the microfluidic technique. The prepared niosomes were characterised using dynamic light scattering (DLS) for their size determination; high-pressure liquid chromatography, HPLC, for drug encapsulation efficiency determination; and the agar diffusion method for the determination of the antibacterial efficacy of the VCM niosomes against Bacillus subtilis. The niosomal formulation was then incorporated into polyvinyl alcohol (PVA) film, and the properties of the oral film were characterised by in vitro assays. The vancomycin-loaded niosomes produced with optimal conditions exhibited small diameter with acceptable polydispersity index, and drug encapsulation efficiency. This study presents multifunctional niosomes loaded with VCM, which demonstrated efficient in vitro activity against Gram-positive bacteria upon the slow release of VCM from niosomes, as demonstrated by the dissolution test. Oral films containing VCM niosomes demonstrated uniform weights and excellent flexibility with high foldability and a rapid disintegration time of 105 ± 12 s to release the niosomal content. This study showed that the microfluidic approach could encapsulate VCM, a peptide in salt form, in surfactant-based niosomal vesicles with a narrow size distribution. The incorporation of niosomes into fast-disintegrating film provides a non-invasive and patient-friendly alternative for treating bacterial infections in the oral cavity, making it a promising approach for dental and systemic applications. Full article

(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)

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17 pages, 716 KiB

Open AccessArticle

Fabrication and Evaluation of Polyhydroxyalkanoate-Based Nanoparticles for Curcumin Delivery in Biomedical Applications

by Fawzia Sha’at, Dana Miu, Mihaela Carmen Eremia, Georgeta Neagu, Adrian Albulescu, Radu Albulescu, Mihaela Deaconu, Mariana Gratiela Vladu and Ramona-Daniela Pavaloiu

Molecules 2025, 30(6), 1216; https://doi.org/10.3390/molecules30061216 - 8 Mar 2025

Viewed by 666

Abstract

This study investigates the fabrication and characterization of polymeric nanoparticles based on polyhydroxyalkanoates (PHAs) loaded with curcumin for biomedical applications. PHAs, biodegradable and biocompatible polymers, were synthesized via bacterial fermentation and used to encapsulate curcumin using the nanoprecipitation method. The resulting nanoparticles were characterized for their particle size, polydispersity index, and encapsulation efficiency, achieving high entrapment rates (above 80%) and nanometric size distribution. Stability assessments demonstrated prolonged structural integrity under storage conditions. In vitro release studies conducted in phosphate-buffered saline at pH 5 and 7.4 revealed sustained drug release profiles. Biocompatibility and cytotoxicity assays using human astrocytes and fibroblasts confirmed the nanoparticles’ safety, while antiproliferative tests on glioblastoma and colon cancer cell lines indicated potential therapeutic efficacy. Additionally, skin irritation and corrosion tests using the EpiDerm™ model classified the formulations as non-irritant and non-corrosive. These findings suggest that PHA-based nanoparticles offer a promising nanocarrier system for curcumin delivery, with potential applications in cancer treatment and regenerative medicine. Future research should focus on optimizing the formulation and evaluating in vivo therapeutic effects. Full article

(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)

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17 pages, 5350 KiB

Open AccessArticle

Near-Infrared Light-Responsive Molybdenum Disulfide Nanosheets for Controlling the Release of Nimodipine as NIR-Drug Delivery System

by Mohamed M. Abdelghafour, Ágota Deák, Keristina Wagdi K. Amin, Zsófia Czimer, Czike Flóra Veronika, Viktória Péter, Róbert Berkecz, Ferenc Bari and László Janovák

Molecules 2025, 30(3), 497; https://doi.org/10.3390/molecules30030497 - 23 Jan 2025

Viewed by 789

Abstract

Here, we present a photothermally triggered drug delivery nanosystem MoS₂-NIMO-CHIT-SH, using the thiolated chitosan (CHIT-SH)-modified molybdenum disulfide (MoS₂) nanosheets as near-infrared (NIR) photo-responsive carriers, loaded with the dihydropyridine calcium antagonist drug Nimodipine (NIMO). Although NIMO is used to treat stroke, migraine, Alzheimer’s disease, cerebrovascular spasms, and hypertension, this drug is poorly water-soluble, with low bioavailability and lack of selectivity. Thus, there is an urgent need for a novel approach to creating NIMO formulations that are safe, effective, and have better solubility and bioavailability. To overcome these problems, we develop a cationic biopolymer functionalized MoS₂ nanosheets as a photothermal drug carrier system to facilitate the NIR light-induced release of NIMO drugs. MoS₂ nanosheets (<150 nm) as NIMO drug carriers are prepared through simple exfoliation of their bulk phase and then functionalized with CHIT-SH biopolymer to increase their physiological stability and biocompatibility. According to the results, MoS₂-NIMO-CHIT-SH nanocomposites show strong NIR absorbance, which makes them a promising candidate for photothermal therapy. Full article

(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)

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17 pages, 3890 KiB

Open AccessArticle

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

Cited by 2 | Viewed by 1562

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-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

Open AccessArticle

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 1564

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 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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42 pages, 7901 KiB

Open AccessReview

Recent Progress in Thiazole, Thiosemicarbazone, and Semicarbazone Derivatives as Antiparasitic Agents Against Trypanosomatids and Plasmodium spp.

by Pamela Souza Tada da Cunha, Ana Luísa Rodriguez Gini, Chung Man Chin, Jean Leandro dos Santos and Cauê Benito Scarim

Molecules 2025, 30(8), 1788; https://doi.org/10.3390/molecules30081788 - 16 Apr 2025

Viewed by 540

Abstract

Neglected tropical diseases (NTDs), including Chagas disease, human African trypanosomiasis (HAT), leishmaniasis, and malaria, remain a major global health challenge, disproportionately affecting low-income populations. Current therapies for these diseases suffer from significant limitations, such as reduced efficacy, high toxicity, and emerging parasite resistance, highlighting the urgent need for new therapeutic strategies. In response, substantial efforts have been directed toward the synthesis of new molecules with improved potency, selectivity, and pharmacokinetic profiles. However, despite many of these compounds exhibiting favorable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles and strong in vitro activity, their translation into in vivo models remains limited. Key challenges include the lack of investment, the absence of fully representative experimental models, and difficulties in extrapolating cell-based assay results to more complex biological systems. In this review, we analyzed the latest advancements (2019–2024) in the development of these compound classes, correlating predictive parameters with their observed biological activity. Among these parameters, we highlighted the partition coefficient (LogP), which measures a compound’s lipophilicity and influences its ability to cross biological membranes, and Caco-2 cell permeability, an in vitro model widely used to predict intestinal drug absorption. Additionally, we prioritized the most promising molecules and structural classes for pharmaceutical development, discussing structure–activity relationships (SARs) and the remaining challenges that must be overcome to enable the clinical application of these compounds in the treatment of NTDs. Full article

(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)

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20 pages, 1761 KiB

Open AccessReview

Nanoparticles for Photodynamic Therapy of Breast Cancer: A Review of Recent Studies

by Dorota Bartusik-Aebisher, Agnieszka Przygórzewska, Paweł Woźnicki and David Aebisher

Molecules 2025, 30(7), 1571; https://doi.org/10.3390/molecules30071571 - 31 Mar 2025

Viewed by 586

Abstract

Photodynamic therapy (PDT) is a therapeutic method based on the interaction between light and a photosensitizer. Supported by nanoparticles, this method represents a promising interdisciplinary approach for the treatment of many diseases. This article reviews the latest 2024 developments in the design and applications of nanoparticles dedicated to stand-alone PDT of breast cancer. Strategies to improve therapeutic efficacy by enhancing reactive oxygen species (ROS) production, precise delivery of photosensitizers and their stabilization in the systemic circulation are discussed, among others. Results from preclinical studies indicate significant improvements in therapeutic efficacy, including inhibition of tumor growth, reduction in metastasis and improvement of the immune microenvironment. The potential of these technologies to expand PDT applications in medicine and the need for further clinical trials to confirm their safety and efficacy are highlighted. Full article

(This article belongs to the Special Issue Molecular Approaches to Drug Discovery and Development)

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18 pages, 4988 KiB

Open AccessReview

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 2 | Viewed by 1852

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 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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