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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 23335

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Special Issue Editor

Prof. Dr. Liming Hu

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Guest Editor

1. Faculty of Environment and Life, Beijing University of Technology, Beijing, China
2. Beijing Key Laboratory of Environmental and Viral Oncology, Beijing 100124, China
Interests: drug synthesis methodology; drug design; protein-ligand interactions

Special Issue Information

Dear Colleagues,

In the last 30 years, rational drug design and molecular targeted drugs have been investigated in the cancer therapy area, making their applications in medical therapies a rapidly expanding field.

This Special Issue on "Drug Discovery and Applications of New Technologies" will highlight new insights into the discovery of new drugs, from the investigation of new targets to the identification of novel small molecules. Contributions to this issue, both in the form of original articles or reviews, may focus on powerful strategies and technological advances in the synthesis of more efficient and selective compounds, new strategies to control solubility and absorption, new approaches to increase stability and improvements regarding the use of combination therapy in oncology and other pathologies, in which therapeutic combinations with less toxic and off-target effects are considered.

We cordially encourage you to submit research articles and reviews for this Special Issue to share your work, knowledge, insights, and recent accomplishments.

Prof. Dr. Liming Hu
Guest Editor

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Keywords

kinase inhibitors
multi-target inhibitor
rational drug design
combination therapy
methodology for drug synthesis
drug delivery
nanomedicine

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Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 185 KiB

Open AccessEditorial

Special Issue “Drug Discovery and Application of New Technologies”

by Sha Hu, Yaxin Li and Liming Hu

Int. J. Mol. Sci. 2024, 25(21), 11756; https://doi.org/10.3390/ijms252111756 - 1 Nov 2024

Viewed by 468

Abstract

Historically, drug discovery and development have proven to be time-consuming and costly, with the process averaging around 15 years and costing approximately USD 2 billion to bring a new small-molecule drug to market [...] Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

Research

Jump to: Editorial, Review

17 pages, 2618 KiB

Open AccessArticle

Synthesis of Antiprotozoal 2-(4-Alkyloxyphenyl)-Imidazolines and Imidazoles and Their Evaluation on Leishmania mexicana and Trypanosoma cruzi

by Jenifer Torres-Jaramillo, René Blöcher, Karla Fabiola Chacón-Vargas, Jorge Hernández-Calderón, Luvia E. Sánchez-Torres, Benjamín Nogueda-Torres and Alicia Reyes-Arellano

Int. J. Mol. Sci. 2024, 25(7), 3673; https://doi.org/10.3390/ijms25073673 - 26 Mar 2024

Cited by 1 | Viewed by 923

Abstract

Twenty 2-(4-alkyloxyphenyl)-imidazolines and 2-(4-alkyloxyphenyl)-imidazoles were synthesized, with the former being synthesized in two steps by using MW and ultrasonication energy, resulting in good to excellent yields. Imidazoles were obtained in moderate yields by oxidizing imidazolines with MnO₂ and MW energy. In response to the urgent need to treat neglected tropical diseases, a set of 2-(4-alkyloxyphenyl)- imidazolines and imidazoles was tested in vitro on Leishmania mexicana and Trypanosoma cruzi. The leishmanicidal activity of ten compounds was evaluated, showing an IC₅₀ < 10 µg/mL. Among these compounds, 27–31 were the most active, with IC₅₀ values < 1 µg/mL (similar to the reference drugs). In the evaluation on epimastigotes of T. cruzi, only 30 and 36 reached an IC₅₀ < 1 µg/mL, showing better inhibition than both reference drugs. However, compounds 29, 33, and 35 also demonstrated attractive trypanocidal activities, with IC₅₀ values < 10 µg/mL, similar to the values for benznidazole and nifurtimox. Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

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26 pages, 4298 KiB

Open AccessArticle

Birinapant Reshapes the Tumor Immunopeptidome and Enhances Antigen Presentation

by Weiyan Zhang, Shenghuan Sun, Wenyuan Zhu, Delan Meng, Weiyi Hu, Siqi Yang, Mingjie Gao, Pengju Yao, Yuhao Wang, Qingsong Wang and Jianguo Ji

Int. J. Mol. Sci. 2024, 25(7), 3660; https://doi.org/10.3390/ijms25073660 - 25 Mar 2024

Viewed by 1748

Abstract

Birinapant, an antagonist of the inhibitor of apoptosis proteins, upregulates MHCs in tumor cells and displays a better tumoricidal effect when used in combination with immune checkpoint inhibitors, indicating that Birinapant may affect the antigen presentation pathway; however, the mechanism remains elusive. Based on high-resolution mass spectrometry and in vitro and in vivo models, we adopted integrated genomics, proteomics, and immunopeptidomics strategies to study the mechanism underlying the regulation of tumor immunity by Birinapant from the perspective of antigen presentation. Firstly, in HT29 and MCF7 cells, Birinapant increased the number and abundance of immunopeptides and source proteins. Secondly, a greater number of cancer/testis antigen peptides with increased abundance and more neoantigens were identified following Birinapant treatment. Moreover, we demonstrate the existence and immunogenicity of a neoantigen derived from insertion/deletion mutation. Thirdly, in HT29 cell-derived xenograft models, Birinapant administration also reshaped the immunopeptidome, and the tumor exhibited better immunogenicity. These data suggest that Birinapant can reshape the tumor immunopeptidome with respect to quality and quantity, which improves the presentation of CTA peptides and neoantigens, thus enhancing the immunogenicity of tumor cells. Such changes may be vital to the effectiveness of combination therapy, which can be further transferred to the clinic or aid in the development of new immunotherapeutic strategies to improve the anti-tumor immune response. Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

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21 pages, 4365 KiB

Open AccessArticle

The Optimization Design of Macrophage Membrane Camouflaging Liposomes for Alleviating Ischemic Stroke Injury through Intranasal Delivery

by Tianshu Liu, Yan Wang, Mengfan Zhang, Jin Zhang, Naijin Kang, Linlin Zheng and Zhiying Ding

Int. J. Mol. Sci. 2024, 25(5), 2927; https://doi.org/10.3390/ijms25052927 - 2 Mar 2024

Cited by 5 | Viewed by 1530

Abstract

Ischemic stroke is associated with a high mortality rate, and effective treatment strategies are currently lacking. In this study, we aimed to develop a novel nano delivery system to treat ischemic stroke via intranasal administration. A three-factor Box–Behnken experimental design was used to optimize the formulation of liposomes co-loaded with Panax notoginseng saponins (PNSs) and Ginsenoside Rg3 (Rg3) (Lip-Rg3/PNS). Macrophage membranes were coated onto the surface of the optimized liposomes to target the ischemic site of the brain. The double-loaded liposomes disguised by macrophage membranes (MM-Lip-Rg3/PNS) were spherical, in a “shell–core” structure, with encapsulation rates of 81.41% (PNS) and 93.81% (Rg3), and showed good stability. In vitro, MM-Lip-Rg3/PNS was taken up by brain endothelial cells via the clathrin-dependent endocytosis and micropinocytosis pathways. Network pharmacology experiments predicted that MM-Lip-Rg3/PNS could regulate multiple signaling pathways and treat ischemic stroke by reducing apoptosis and inflammatory responses. After 14 days of treatment with MM-Lip-Rg3/PNS, the survival rate, weight, and neurological score of middle cerebral artery occlusion (MCAO) rats significantly improved. The hematoxylin and eosin (H&E) and TUNEL staining results showed that MM-Lip-Rg3/PNS can reduce neuronal apoptosis and inflammatory cell infiltration and protect the ischemic brain. In vivo biological experiments have shown that free Rg3, PNS, and MM-Lip-Rg3/PNS can alleviate inflammation and apoptosis, especially MM-Lip-Rg3/PNS, indicating that biomimetic liposomes can improve the therapeutic effects of drugs. Overall, MM-Lip-Rg3/PNS is a potential biomimetic nano targeted formulation for ischemic stroke therapy. Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

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19 pages, 4668 KiB

Open AccessArticle

Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain

by Jingyi Bai, Xi Li, Jun Zhao, Huifang Zong, Yuan Yuan, Lei Wang, Xiaoshuai Zhang, Yong Ke, Lei Han, Jianrong Xu, Buyong Ma, Baohong Zhang and Jianwei Zhu

Int. J. Mol. Sci. 2024, 25(3), 1593; https://doi.org/10.3390/ijms25031593 - 27 Jan 2024

Cited by 2 | Viewed by 1698

Abstract

Amyloidosis involves the deposition of misfolded proteins. Even though it is caused by different pathogenic mechanisms, in aggregate, it shares similar features. Here, we tested and confirmed a hypothesis that an amyloid antibody can be engineered by a few mutations to target a different species. Amyloid light chain (AL) and β-amyloid peptide (Aβ) are two therapeutic targets that are implicated in amyloid light chain amyloidosis and Alzheimer’s disease, respectively. Though crenezumab, an anti-Aβ antibody, is currently unsuccessful, we chose it as a model to computationally design and prepare crenezumab variants, aiming to discover a novel antibody with high affinity to AL fibrils and to establish a technology platform for repurposing amyloid monoclonal antibodies. We successfully re-engineered crenezumab to bind both Aβ42 oligomers and AL fibrils with high binding affinities. It is capable of reversing Aβ42-oligomers-induced cytotoxicity, decreasing the formation of AL fibrils, and alleviating AL-fibrils-induced cytotoxicity in vitro. Our research demonstrated that an amyloid antibody could be engineered by a few mutations to bind new amyloid sequences, providing an efficient way to reposition a therapeutic antibody to target different amyloid diseases. Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

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19 pages, 10940 KiB

Open AccessArticle

Dynamic Dimerization of Chemokine Receptors and Potential Inhibitory Role of Their Truncated Isoforms Revealed through Combinatorial Prediction

by Mengke Li, Rui Qing, Fei Tao, Ping Xu and Shuguang Zhang

Int. J. Mol. Sci. 2023, 24(22), 16266; https://doi.org/10.3390/ijms242216266 - 13 Nov 2023

Cited by 3 | Viewed by 2042

Abstract

Chemokine receptors play crucial roles in fundamental biological processes. Their malfunction may result in many diseases, including cancer, autoimmune diseases, and HIV. The oligomerization of chemokine receptors holds significant functional implications that directly affect their signaling patterns and pharmacological responses. However, the oligomerization patterns of many chemokine receptors remain poorly understood. Furthermore, several chemokine receptors have highly truncated isoforms whose functional role is not yet clear. Here, we computationally show homo- and heterodimerization patterns of four human chemokine receptors, namely CXCR2, CXCR7, CCR2, and CCR7, along with their interaction patterns with their respective truncated isoforms. By combining the neural network-based AlphaFold2 and physics-based protein–protein docking tool ClusPro, we predicted 15 groups of complex structures and assessed the binding affinities in the context of atomistic molecular dynamics simulations. Our results are in agreement with previous experimental observations and support the dynamic and diverse nature of chemokine receptor dimerization, suggesting possible patterns of higher-order oligomerization. Additionally, we uncover the strong potential of truncated isoforms to block homo- and heterodimerization of chemokine receptors, also in a dynamic manner. Our study provides insights into the dimerization patterns of chemokine receptors and the functional significance of their truncated isoforms. Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

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15 pages, 3045 KiB

Open AccessArticle

Generation of a Novel SORT1×HER2 Bispecific Antibody–Drug Conjugate Targeting HER2-Low-Expression Tumor

by Weiliang Zhuang, Wei Zhang, Lei Wang, Liping Xie, Jun Feng, Baohong Zhang and Youjia Hu

Int. J. Mol. Sci. 2023, 24(22), 16056; https://doi.org/10.3390/ijms242216056 - 7 Nov 2023

Cited by 7 | Viewed by 2605

Abstract

Human epidermal growth factor receptor 2 (HER2) is considered an ideal antibody–drug conjugate (ADC) target because the gene is overexpressed in many tumors compared to normal tissues. Multiple anti-HER2 ADCs conjugated with different toxic payloads bring benefits to patients with high HER2 expression. However, HER2-targeted ADC technology needs further optimization to improve its effect for the treatment of patients with low HER2 expression. We hypothesized that bispecific antibody–drug conjugate (bsADC) targeting HER2 and Sortilin-1 (SORT1) would overcome this limitation. SORT1 is a suitable target for pairing with HER2 to generate a bispecific antibody (BsAb) since the gene is co-expressed with HER2 in tumors and possesses rapid internalization. We developed a BsAb (bsSORT1×HER2) that exhibited strong binding and internalization activity on HER2-low-expression tumor cells and facilitated higher HER2 degradation. The bsSORT1×HER2 was further conjugated with DXd to generate a bsADC (bsSORT1×HER2-DXd) that showed strong cytotoxicity on HER2-low-expression tumor cells and antitumor efficacy in an MDA-MB-231 xenograft mice model. These results demonstrated that employment of a SORT1×HER2-targeted bsADC may be promising to improve the antitumor efficacy of HER2-targeted ADC for the treatment of tumors with low HER2 expression. Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

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18 pages, 2723 KiB

Open AccessArticle

Identification and Isolation of α-Glucosidase Inhibitors from Siraitia grosvenorii Roots Using Bio-Affinity Ultrafiltration and Comprehensive Chromatography

by Fenglai Lu, Jiayi Sun, Xiaohua Jiang, Jingru Song, Xiaojie Yan, Qinghu Teng and Dianpeng Li

Int. J. Mol. Sci. 2023, 24(12), 10178; https://doi.org/10.3390/ijms241210178 - 15 Jun 2023

Cited by 7 | Viewed by 4918

Abstract

The discovery of bioactive compounds from medicinal plants has played a crucial role in drug discovery. In this study, a simple and efficient method utilizing affinity-based ultrafiltration (UF) coupled with high-performance liquid chromatography (HPLC) was developed for the rapid screening and targeted separation of α-glucosidase inhibitors from Siraitia grosvenorii roots. First, an active fraction of S. grosvenorii roots (SGR2) was prepared, and 17 potential α-glucosidase inhibitors were identified based on UF-HPLC analysis. Second, guided by UF-HPLC, a combination of MCI gel CHP-20P column chromatography, high-speed counter-current countercurrent chromatography, and preparative HPLC were conducted to isolate the compounds producing active peaks. Sixteen compounds were successfully isolated from SGR2, including two lignans and fourteen cucurbitane-type triterpenoids. The structures of the novel compounds (4, 6, 7, 8, 9, and 11) were elucidated using spectroscopic methods, including one- and two-dimensional nuclear magnetic resonance spectroscopy and high-resolution electrospray ionization mass spectrometry. Finally, the α-glucosidase inhibitory activities of the isolated compounds were verified via enzyme inhibition assays and molecular docking analysis, all of which were found to exhibit certain inhibitory activity. Compound 14 exhibited the strongest inhibitory activity, with an IC₅₀ value of 430.13 ± 13.33 μM, which was superior to that of acarbose (1332.50 ± 58.53 μM). The relationships between the structures of the compounds and their inhibitory activities were also investigated. Molecular docking showed that the highly active inhibitors interacted with α-glucosidase through hydrogen bonds and hydrophobic interactions. Our results demonstrate the beneficial effects of S. grosvenorii roots and their constituents on α-glucosidase inhibition. Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

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12 pages, 3443 KiB

Open AccessArticle

Synthesis of Novel Antimicrobial CHX-CaCl₂ Coatings on Maxillofacial Fixatures for Infection Prevention

by Hawraa F. Alostath, Domniki Chatzopoulou, Simon Holmes, David Gould, Gleb Sukhorukov and Michael J. Cattell

Int. J. Mol. Sci. 2023, 24(12), 9801; https://doi.org/10.3390/ijms24129801 - 6 Jun 2023

Cited by 1 | Viewed by 2223

Abstract

Maxillofacial surgery placement of fixatures (Leonard Buttons, LB) at close proximity to surgical incisions provides a potential reservoir as a secondary local factor to advanced periodontal disease, with bacterial formation around failed fixatures implicating plaque. To address infection rates, we aimed to surface coat LB and Titanium (Ti) discs using a novel form of chlorhexidine (CHX), CHX-CaCl₂ and 0.2% CHX digluconate mouthwash as a comparison. CHX-CaCl₂ coated, double-coated and mouthwash coated LB and Ti discs were transferred to 1 mL artificial saliva (AS) at specified time points, and UV-Visible spectroscopy (254 nm) was used to measure CHX release. The zone of inhibition (ZOI) was measured using collected aliquots against bacterial strains. Specimens were characterized using Energy Dispersive X-ray Spectroscopy (EDS), X-ray Diffraction (XRD) and Scanning Electron Microscopy (SEM). SEM displayed copious dendritic crystals on LB/ Ti disc surfaces. Drug release from double-coated CHX-CaCl₂ was 14 days (Ti discs) and 6 days (LB) above MIC, compared to the comparison group (20 min). The ZOI for the CHX-CaCl₂ coated groups was significantly different within groups (p < 0.05). CHX-CaCl₂ surface crystallization is a new drug technology for controlled and sustained CHX release; its antibacterial effectiveness makes this drug an ideal adjunct following clinical and surgical procedures to maintain oral hygiene and prevent surgical site infections. Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

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17 pages, 5076 KiB

Open AccessArticle

Prediction and Verification of Curcumin as a Potential Drug for Inhibition of PDCoV Replication in LLC-PK1 Cells

by Xuefei Wang, Xue Wang, Jialu Zhang, Qiang Shan, Yaohong Zhu, Chuang Xu and Jiufeng Wang

Int. J. Mol. Sci. 2023, 24(6), 5870; https://doi.org/10.3390/ijms24065870 - 20 Mar 2023

Cited by 5 | Viewed by 2275

Abstract

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus (CoV) that causes lethal watery diarrhea in neonatal pigs and poses economic and public health burdens. Currently, there are no effective antiviral agents against PDCoV. Curcumin is the active ingredient extracted from the rhizome of turmeric, which has a potential pharmacological value because it exhibits antiviral properties against several viruses. Here, we described the antiviral effect of curcumin against PDCoV. At first, the potential relationships between the active ingredients and the diarrhea-related targets were predicted through a network pharmacology analysis. Twenty-three nodes and 38 edges were obtained using a PPI analysis of eight compound-targets. The action target genes were closely related to the inflammatory and immune related signaling pathways, such as the TNF signaling pathway, Jak-STAT signaling pathway, and so on. Moreover, IL-6, NR3C2, BCHE and PTGS2 were identified as the most likely targets of curcumin by binding energy and 3D protein-ligand complex analysis. Furthermore, curcumin inhibited PDCoV replication in LLC-PK1 cells at the time of infection in a dose-dependent way. In poly (I:C) pretreated LLC-PK1 cells, PDCoV reduced IFN-β production via the RIG-I pathway to evade the host’s antiviral innate immune response. Meanwhile, curcumin inhibited PDCoV-induced IFN-β secretion by inhibiting the RIG-I pathway and reduced inflammation by inhibiting IRF3 or NF-κB protein expression. Our study provides a potential strategy for the use of curcumin in preventing diarrhea caused by PDCoV in piglets. Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

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Review

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32 pages, 2625 KiB

Open AccessReview

Recent Progress of Spectroscopic Probes for Peroxynitrite and Their Potential Medical Diagnostic Applications

by Zixin Liu, Shanyan Mo, Zhenming Hao and Liming Hu

Int. J. Mol. Sci. 2023, 24(16), 12821; https://doi.org/10.3390/ijms241612821 - 15 Aug 2023

Cited by 1 | Viewed by 1942

Abstract

Peroxynitrite (ONOO⁻) is a crucial reactive oxygen species that plays a vital role in cellular signal transduction and homeostatic regulation. Determining and visualizing peroxynitrite accurately in biological systems is important for understanding its roles in physiological and pathological activity. Among the various detection methods, fluorescent probe-based spectroscopic detection offers real-time and minimally invasive detection, high sensitivity and selectivity, and easy structural and property modification. This review categorizes fluorescent probes by their fluorophore structures, highlighting their chemical structures, recognition mechanisms, and response behaviors in detail. We hope that this review could help trigger novel ideas for potential medical diagnostic applications of peroxynitrite-related molecular diseases. Full article

(This article belongs to the Special Issue Drug Discovery and Application of New Technologies)

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