Emerging Aspects in Drug Discovery

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31 pages, 1656 KiB

Open AccessReview

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

Cited by 8 | Viewed by 7314

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 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

Open AccessArticle

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 - 6 Jan 2024

Viewed by 2132

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 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

Open AccessArticle

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 - 8 Jul 2023

Cited by 1 | Viewed by 2132

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 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

Open AccessArticle

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 7 | Viewed by 2320

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 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

Open AccessArticle

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 4 | Viewed by 2993

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 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 (K_D = 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

Open AccessArticle

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 8 | Viewed by 4059

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 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

Open AccessReview

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 - 8 Sep 2022

Cited by 14 | Viewed by 6591

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 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

Open AccessArticle

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 8 | Viewed by 3156

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 pyridobenzimidazole linkers were synthesized yielding compounds 5–8 and 10–14, 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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Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Antibiotics antibiotics	4.3	7.3	2012	15.8 Days	CHF 2900
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900
Magnetochemistry magnetochemistry	2.6	3.9	2015	15.8 Days	CHF 2200
Marine Drugs marinedrugs	4.9	9.6	2003	13.7 Days	CHF 2900
Molecules molecules	4.2	7.4	1996	15.1 Days	CHF 2700

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