Topic Editors

Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, CO 80045, USA
Department of Biochemistry and Molecular Genetics, and RNA BioScience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA

Emerging Aspects in Drug Discovery

Abstract submission deadline
closed (1 September 2023)
Manuscript submission deadline
closed (1 December 2023)
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Topic Information

Dear Colleagues,

With the large number of diseases still present worldwide that remain difficult to treat, drug discovery is a pressing endeavor. However, finding effective therapeutic agents remains onerous and time consuming. How could new approaches, technologies, and perhaps targets facilitate the process of identifying, characterizing, developing, and marketing drugs? This Topic on “Emerging Aspects in Drug Discovery” welcomes submissions of research and review articles that touch upon—but are not limited to—the following areas: novel screening strategies and synthetic chemistry approaches, as well as emerging drug targets which can be any macromolecule, RNA, DNA, or protein. We hope this Topic will serve as a springboard for a continuous increase in the rates of approved drugs for treating different diseases.

Dr. Morkos Henen
Dr. Quentin Vicens
Dr. Beat Rolf Vögeli
Topic Editors

Keywords

  • compound development
  • drug discovery
  • high-throughput screening
  • natural compounds
  • structure–activity relationship
  • structure-based drug design
  • synthetic chemistry
  • target identification and validation

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Antibiotics
antibiotics
4.8 5.5 2012 13.7 Days CHF 2900
International Journal of Molecular Sciences
ijms
5.6 7.8 2000 16.3 Days CHF 2900
Magnetochemistry
magnetochemistry
2.7 3.5 2015 15.8 Days CHF 2700
Marine Drugs
marinedrugs
5.4 9.6 2003 14 Days CHF 2900
Molecules
molecules
4.6 6.7 1996 14.6 Days CHF 2700

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Published Papers (8 papers)

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31 pages, 1656 KiB  
Review
Anti-PD-L1-Based Bispecific Antibodies Targeting Co-Inhibitory and Co-Stimulatory Molecules for Cancer Immunotherapy
by Qiaohong Geng and Peifu Jiao
Molecules 2024, 29(2), 454; https://doi.org/10.3390/molecules29020454 - 17 Jan 2024
Viewed by 1500
Abstract
Targeting PD-L1 via monospecific antibodies has shown durable clinical benefits and long-term remissions where patients exhibit no clinical cancer signs for many years after treatment. However, the durable clinical benefits and long-term remissions by anti-PD-L1 monotherapy have been limited to a small fraction [...] Read more.
Targeting PD-L1 via monospecific antibodies has shown durable clinical benefits and long-term remissions where patients exhibit no clinical cancer signs for many years after treatment. However, the durable clinical benefits and long-term remissions by anti-PD-L1 monotherapy have been limited to a small fraction of patients with certain cancer types. Targeting PD-L1 via bispecific antibodies (referred to as anti-PD-L1-based bsAbs) which can simultaneously bind to both co-inhibitory and co-stimulatory molecules may increase the durable antitumor responses in patients who would not benefit from PD-L1 monotherapy. A growing number of anti-PD-L1-based bsAbs have been developed to fight against this deadly disease. This review summarizes recent advances of anti-PD-L1-based bsAbs for cancer immunotherapy in patents and literatures, and discusses their anti-tumor efficacies in vitro and in vivo. Over 50 anti-PD-L1-based bsAbs targeting both co-inhibitory and co-stimulatory molecules have been investigated in biological testing or in clinical trials since 2017. At least eleven proteins, such as CTLA-4, LAG-3, PD-1, PD-L2, TIM-3, TIGIT, CD28, CD27, OX40, CD137, and ICOS, are involved in these investigations. Twenty-two anti-PD-L1-based bsAbs are being evaluated to treat various advanced cancers in clinical trials, wherein the indications include NSCLC, SNSCLC, SCLC, PDA, MBNHL, SCCHN, UC, EC, TNBC, CC, and some other malignancies. The released data from clinical trials indicated that most of the anti-PD-L1-based bsAbs were well-tolerated and showed promising antitumor efficacy in patients with advanced solid tumors. However, since the approved and investigational bsAbs have shown much more significant adverse reactions compared to PD-L1 monospecific antibodies, anti-PD-L1-based bsAbs may be further optimized via molecular structure modification to avoid or reduce these adverse reactions. Full article
(This article belongs to the Topic Emerging Aspects in Drug Discovery)
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15 pages, 2737 KiB  
Article
Fluorescent Ligand Equilibrium Displacement: A High-Throughput Method for Identification of FMN Riboswitch-Binding Small Molecules
by Elizabeth D. Tidwell, Ingrid R. Kilde, Suada Leskaj and Markos Koutmos
Int. J. Mol. Sci. 2024, 25(2), 735; https://doi.org/10.3390/ijms25020735 - 06 Jan 2024
Viewed by 866
Abstract
Antibiotic resistance remains a pressing global concern, with most antibiotics targeting the bacterial ribosome or a limited range of proteins. One class of underexplored antibiotic targets is bacterial riboswitches, structured RNA elements that regulate key biosynthetic pathways by binding a specific ligand. We [...] Read more.
Antibiotic resistance remains a pressing global concern, with most antibiotics targeting the bacterial ribosome or a limited range of proteins. One class of underexplored antibiotic targets is bacterial riboswitches, structured RNA elements that regulate key biosynthetic pathways by binding a specific ligand. We developed a methodology termed Fluorescent Ligand Equilibrium Displacement (FLED) to rapidly discover small molecules that bind the flavin mononucleotide (FMN) riboswitch. FLED leverages intrinsically fluorescent FMN and the quenching effect on RNA binding to create a label-free, in vitro method to identify compounds that can bind the apo population of riboswitch in a system at equilibrium. The response difference between known riboswitch ligands and controls demonstrates the robustness of the method for high-throughput screening. An existing drug discovery library that was screened using FLED resulted in a final hit rate of 0.67%. The concentration response of each hit was determined and revealed a variety of approximate effective concentration values. Our preliminary screening data support the use of FLED to identify small molecules for medicinal chemistry development as FMN riboswitch-targeted antibiotic compounds. This robust, label-free, and cell-free method offers a strong alternative to other riboswitch screening methods and can be adapted to a variety of laboratory setups. Full article
(This article belongs to the Topic Emerging Aspects in Drug Discovery)
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15 pages, 1693 KiB  
Article
Influence of SGLT1 Sugar Uptake Inhibitors on Water Transport
by Marko Sever and Franci Merzel
Molecules 2023, 28(14), 5295; https://doi.org/10.3390/molecules28145295 - 08 Jul 2023
Viewed by 909
Abstract
Sodium glucose cotransporters (SGLTs) are cotransporters located in the cell membrane of various epithelia that uptake glucose or galactose and sodium into the cell. Its founding member, SGLT1, represents a major pharmaceutically relevant target protein for development of new antidiabetic drugs, in addition [...] Read more.
Sodium glucose cotransporters (SGLTs) are cotransporters located in the cell membrane of various epithelia that uptake glucose or galactose and sodium into the cell. Its founding member, SGLT1, represents a major pharmaceutically relevant target protein for development of new antidiabetic drugs, in addition to being the target protein of the oral rehydration therapy. Previous studies focused primarily on the transport of substrates and ions, while our study focuses on the effect of water transport. SGLT1 is implicated in the absorption of water, yet the exact mechanism of how the water absorption occurs or how inhibitors of SGLT1, such as phlorizin, are able to inhibit it is still unclear. Here we present a comprehensive study based on molecular dynamics simulations with the aim of determining the influence of the energetic and dynamic properties of SGLT1, which are influenced by selected sugar uptake inhibitors on water permeation. Full article
(This article belongs to the Topic Emerging Aspects in Drug Discovery)
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15 pages, 1826 KiB  
Article
Group I Intron as a Potential Target for Antifungal Compounds: Development of a Trans-Splicing High-Throughput Screening Strategy
by Bastien Malbert, Virginie Labaurie, Cécile Dorme and Eric Paget
Molecules 2023, 28(11), 4460; https://doi.org/10.3390/molecules28114460 - 31 May 2023
Cited by 3 | Viewed by 1264
Abstract
The search for safe and efficient new antifungal compounds for agriculture has led to more efforts in finding new modes of action. This involves the discovery of new molecular targets, including coding and non-coding RNA. Rarely found in plants and animals but present [...] Read more.
The search for safe and efficient new antifungal compounds for agriculture has led to more efforts in finding new modes of action. This involves the discovery of new molecular targets, including coding and non-coding RNA. Rarely found in plants and animals but present in fungi, group I introns are of interest as their complex tertiary structure may allow selective targeting using small molecules. In this work, we demonstrate that group I introns present in phytopathogenic fungi have a self-splicing activity in vitro that can be adapted in a high-throughput screening to find new antifungal compounds. Ten candidate introns from different filamentous fungi were tested and one group ID intron found in F. oxysporum showed high self-splicing efficiency in vitro. We designed the Fusarium intron to act as a trans-acting ribozyme and used a fluorescence-based reporter system to monitor its real time splicing activity. Together, these results are opening the way to study the druggability of such introns in crop pathogen and potentially discover small molecules selectively targeting group I introns in future high-throughput screenings. Full article
(This article belongs to the Topic Emerging Aspects in Drug Discovery)
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24 pages, 8379 KiB  
Article
A Novel Rabbit Anti-Myoglobin Monoclonal Antibody’s Potential Application in Rhabdomyolysis Associated Acute Kidney Injury
by Xinyue Wang, Ou Qiao, Lu Han, Ning Li and Yanhua Gong
Int. J. Mol. Sci. 2023, 24(9), 7822; https://doi.org/10.3390/ijms24097822 - 25 Apr 2023
Cited by 2 | Viewed by 1746
Abstract
Myoglobin (Mb) is the main constituent of vertebrate skeletal muscle and myocardium and plays an essential role in oxygen binding, storage, transport, and earliest disease diagnosis. This study focuses on preparing the novel recombinant rabbit anti-Mb monoclonal antibody and applying it to a [...] Read more.
Myoglobin (Mb) is the main constituent of vertebrate skeletal muscle and myocardium and plays an essential role in oxygen binding, storage, transport, and earliest disease diagnosis. This study focuses on preparing the novel recombinant rabbit anti-Mb monoclonal antibody and applying it to a diagnosis of Mb deposition in rhabdomyolysis-associated acute kidney injury (RM-AKI). The full-length coding sequence of rat Mb was cloned and expressed, and the high-quality and titer rabbit anti-Mb polyclonal antibodies were produced by the immunogen His-Mb fusion protein. A new hybridoma cell was obtained by hybridoma screening technology. With the help of DNA sequencing and a molecular clonal, anti-Mb monoclonal antibody heavy and light chains expression plasmid was constructed. Finally, the recombinant rabbit anti-Mb monoclonal antibody with extraordinarily high affinity (KD = 1.21 pM) was obtained. Meanwhile, it had broad species reactivity (mouse, rat, human, and horse) and good tissue specificity (skeletal muscle and myocardium). It also had a very good performance in western blotting, immunohistochemistry, and immunofluorescence assay to detect the Mb level in the kidney, myocardium, and skeletal muscle of RM-AKI. This study will be significantly helpful for Mb-associated disease diagnosis, and pathogenesis exploration, and further may act as a neutralizing antibody for disease treatment. Full article
(This article belongs to the Topic Emerging Aspects in Drug Discovery)
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10 pages, 1353 KiB  
Article
Machine Learning Models to Predict Protein–Protein Interaction Inhibitors
by Bárbara I. Díaz-Eufracio and José L. Medina-Franco
Molecules 2022, 27(22), 7986; https://doi.org/10.3390/molecules27227986 - 17 Nov 2022
Cited by 3 | Viewed by 2718
Abstract
Protein–protein interaction (PPI) inhibitors have an increasing role in drug discovery. It is hypothesized that machine learning (ML) algorithms can classify or identify PPI inhibitors. This work describes the performance of different algorithms and molecular fingerprints used in chemoinformatics to develop a classification [...] Read more.
Protein–protein interaction (PPI) inhibitors have an increasing role in drug discovery. It is hypothesized that machine learning (ML) algorithms can classify or identify PPI inhibitors. This work describes the performance of different algorithms and molecular fingerprints used in chemoinformatics to develop a classification model to identify PPI inhibitors making the codes freely available to the community, particularly the medicinal chemistry research groups working with PPI inhibitors. We found that classification algorithms have different performances according to various features employed in the training process. Random forest (RF) models with the extended connectivity fingerprint radius 2 (ECFP4) had the best classification abilities compared to those models trained with ECFP6 o MACCS keys (166-bits). In general, logistic regression (LR) models had lower performance metrics than RF models, but ECFP4 was the representation most appropriate for LR. ECFP4 also generated models with high-performance metrics with support vector machines (SVM). We also constructed ensemble models based on the top-performing models. As part of this work and to help non-computational experts, we developed a pipeline code freely available. Full article
(This article belongs to the Topic Emerging Aspects in Drug Discovery)
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15 pages, 3445 KiB  
Review
ESKAPE Pathogens: Looking at Clp ATPases as Potential Drug Targets
by Tehrim Motiwala, Qiniso Mthethwa, Ikechukwu Achilonu and Thandeka Khoza
Antibiotics 2022, 11(9), 1218; https://doi.org/10.3390/antibiotics11091218 - 08 Sep 2022
Cited by 6 | Viewed by 4282
Abstract
Bacterial antibiotic resistance is rapidly growing globally and poses a severe health threat as the number of multidrug resistant (MDR) and extensively drug-resistant (XDR) bacteria increases. The observed resistance is partially due to natural evolution and to a large extent is attributed to [...] Read more.
Bacterial antibiotic resistance is rapidly growing globally and poses a severe health threat as the number of multidrug resistant (MDR) and extensively drug-resistant (XDR) bacteria increases. The observed resistance is partially due to natural evolution and to a large extent is attributed to antibiotic misuse and overuse. As the rate of antibiotic resistance increases, it is crucial to develop new drugs to address the emergence of MDR and XDR pathogens. A variety of strategies are employed to address issues pertaining to bacterial antibiotic resistance and these strategies include: (1) the anti-virulence approach, which ultimately targets virulence factors instead of killing the bacterium, (2) employing antimicrobial peptides that target key proteins for bacterial survival and, (3) phage therapy, which uses bacteriophages to treat infectious diseases. In this review, we take a renewed look at a group of ESKAPE pathogens which are known to cause nosocomial infections and are able to escape the bactericidal actions of antibiotics by reducing the efficacy of several known antibiotics. We discuss previously observed escape mechanisms and new possible therapeutic measures to combat these pathogens and further suggest caseinolytic proteins (Clp) as possible therapeutic targets to combat ESKAPE pathogens. These proteins have displayed unmatched significance in bacterial growth, viability and virulence upon chronic infection and under stressful conditions. Furthermore, several studies have showed promising results with targeting Clp proteins in bacterial species, such as Mycobacterium tuberculosis, Staphylococcus aureus and Bacillus subtilis. Full article
(This article belongs to the Topic Emerging Aspects in Drug Discovery)
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24 pages, 6879 KiB  
Article
New Benzimidazoles Targeting Breast Cancer: Synthesis, Pin1 Inhibition, 2D NMR Binding, and Computational Studies
by Samira Nashaat, Morkos A. Henen, Shahenda M. El-Messery and Hassan Eisa
Molecules 2022, 27(16), 5245; https://doi.org/10.3390/molecules27165245 - 17 Aug 2022
Cited by 3 | Viewed by 2047
Abstract
Benzimidazole derivatives are known to be key players in the development of novel anticancer agents. Herein, we aimed to synthesize novel derivatives to target breast cancer. A new series of benzimidazole derivatives conjugated with either six- and five-membered heterocyclic ring or pyrazanobenzimidazoles and [...] Read more.
Benzimidazole derivatives are known to be key players in the development of novel anticancer agents. Herein, we aimed to synthesize novel derivatives to target breast cancer. A new series of benzimidazole derivatives conjugated with either six- and five-membered heterocyclic ring or pyrazanobenzimidazoles and pyridobenzimidazole linkers were synthesized yielding compounds 58 and 1014, respectively. Structure elucidation of the newly synthesized compounds was achieved through microanalytical analyses and different spectroscopic techniques (1H, 13C-APT and 1H–1H COSY and IR) in addition to mass spectrometry. A biological study for the newly synthesized compounds was performed against breast cancer cell lines (MCF-7), and the most active compounds were further subjected to normal Human lung fibroblast (WI38) which indicates their safety. It was found that most of them exhibit high cytotoxic activity against breast cancer (MCF-7) and low cytotoxic activity against normal (WI38) cell lines. Compounds 5, 8, and 12, which possess the highest anti-breast cancer activity against the MCF-7 cell line, were selected for Pin1 inhibition assay using tannic acid as a reference drug control. Compound 8 was examined for its effect on cell cycle progression and its ability to apoptosis induction. Mechanistic evaluation of apoptosis induction was demonstrated by triggering intrinsic apoptotic pathways via inducing ROS accumulation, increasing Bax, decreasing Bcl-2, and activation of caspases 6, 7, and 9. Binding to 15N-labeled Pin1 enzyme was performed using state-of-the-art 15N–1H HSQC NMR experiments to describe targeting breast cancer on a molecular level. In conclusion, the NMR results demonstrated chemical shift perturbation (peak shifting or peak disappearance) upon adding compound 12 indicating potential binding. Molecular docking using ‘Molecular Operating Environment’ software was extremely useful to elucidate the binding mode of active derivatives via hydrogen bonding. Full article
(This article belongs to the Topic Emerging Aspects in Drug Discovery)
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