Drug Development Research最新文献

The central nervous system is affected by multiple sclerosis (MS), a chronic autoimmune illness characterized by axonal destruction, demyelination, and inflammation. This article summarizes the state of the field, highlighting its complexity and significant influence on people's quality of life. The research employs a network pharmacological approach, integrating systems biology, bioinformatics, and pharmacology to identify biomarkers associated with MS. Utilizing Nelumbo Nucifera (Lotus) seeds, the study involves toxicity assessments, biomolecule screening, and target prediction. Advanced computational methodologies are employed, including molecular docking and dynamic simulations, to assess potential therapeutic interactions. Biomolecule screening identifies eight active compounds from Lotus seeds, including Anonaine and Liriodenine. Target prediction reveals 264 common targets with MS-related genes. Protein-protein interaction analysis establishes a complex network, identifying central targets like SRC and AKT1. Bioinformatics enrichment analysis uncovers potential therapeutic candidates and pathways. A Biomolecule-Target-Pathway network diagram visualizes interactions, with Anonaine and Liriodenine exhibiting strong binding affinities in molecular docking studies. Molecular dynamics simulations provide insights into dynamic interactions. In conclusion, through advanced computational techniques, it unveils molecular interactions, potential therapies, and pathways, bridging predictions with practical applications. Anonaine and Liriodenine show promise in curbing MS biomarkers.

Epilepsy affects at least 1% of the global population of all socioeconomic backgrounds. Data obtained from previous studies suggest the role of mTOR signaling in epileptogenesis. The present study aimed to investigate the hypothesis that mTOR inhibitor sulfamethizole might produce antiepileptic effects in pentylenetetrazole (PTZ)-induced kindling seizures in mice. For induction of kindling, mice were administered 40 mg/kg PTZ on alternate days for 13 days. The severity of kindling was analyzed using a seizure intensity score. Rotarod performance, actophotometer, and chimney tests were performed to check muscle coordination and locomotor functions. mTOR and IL-6 levels were measured in the brain homogenate. Histological analyses were done using hematoxylin–eosin and cresyl violet stains. Sulfamethizole was administered daily at 10 and 50 mg/kg doses. PTZ administration resulted in kindling seizures in the PTZ-veh group. In addition, mice from the PTZ-veh group showed decreased fall time in rotarod performance, reduced locomotor activity, and failed chimney tests. mTOR and IL-6 levels were also increased in the brain, along with neuronal degeneration and a decreased layer of neuronal cells in the hippocampus. Treatment with sulfamethizole at 50 mg/kg significantly ameliorated seizure intensity score, seizure latency and duration, muscle coordination, and locomotor functions compared to the PTZ-veh group. It also downregulated brain mTOR and IL-6 expression significantly. In conclusion, sulfamethizole showed antiepileptic activity against PTZ-induced kindling seizure in mice via mTOR inhibition.

Poor selectivity to tumor cells is a major drawback in the clinical application of the antitumor drug docetaxel (DTX). Peptide–drug conjugates (PDCs) constructed by modifying antitumor drugs with peptide ligands that have high affinity to certain overexpressed receptors in tumor cells are increasingly assessed for their possibility of tumor-selective drug delivery. In the present research, DTX is condensed with 3-(pyridin-2-yldisulfanyl) propanoic acid via ester bond to obtain the intermediate Py-SS-DTX. Two conjugates GSS-DTX and RGDC-SS-DTX were obtained by conjugation of Py-SS-DTX with glutathione (GSH) and RGDC peptide through a thiol-disulfide exchange reaction. Afterwards, these two peptide–DTX conjugates were characterized by proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, and high-resolution mass spectrometry. The GSS-DTX and RGDC-SS-DTX were further evaluated in terms of drug release, cell cycle inhibition, cell apoptosis, and cytotoxicity. The results show that both the GSS-DTX and RGDC-SS-DTX exhibit reduction-responsive drug release and RGDC-SS-DTX exhibit higher reduction-responsiveness. The in vitro antitumor activity study shows that RGDC-SS-DTX exhibits enhanced G2/M phase arrest, cell apoptosis rate, and cytotoxicity as compared to GSS-DTX and free DTX. Besides, RGDC-SS-DTX shows reduced cytotoxicity on normal cells as compared to free DTX. The RGDC-SS-DTX synthesized in this study represents a novel DTX conjugate to effectively and selectively inhibit tumor cells.

The remarkable clinical success of third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has significantly advanced the treatment landscape for non-small-cell lung cancer (NSCLC). However, the emergence of the tertiary point mutation C797S poses a substantial obstacle to their clinical efficacy, leading to a dearth of FDA-approved targeted therapies for patients harboring this mutation. Addressing this pressing clinical challenge necessitates the development of novel therapeutic agents targeting the clinically challenging EGFR mutation. This review delves into the design strategies, antitumor activity, and crucial protein–drug interactions of recently introduced Orthoallosteric fourth-generation EGFR-TKIs. These inhibitors are distinguished by their ability to simultaneously engage both the canonical orthosteric (ATP) binding site and the allosteric site. By shedding light on these key aspects, the review serves as a valuable resource for medicinal chemists, empowering them to propel the advancement of fourth-generation EGFR inhibitors.

Five series of new 1,3,4-thiadiazole hybrids were designed and synthesized as promising EGFR inhibitors. Three human cancer cell lines were employed for testing each hybrid's in vitro antiproliferative efficacy; colon HCT-116, liver HepG-2 and breast MCF-7 using MTT assay. Comparing compound 9a to the reference doxorubicin, 9a shown superior activity to that of Dox with respect to MCF-7 (IC₅₀ 3.31 µM) while being secure for normal cells WI-38 (IC₅₀ = 43.99 µM). Further evaluation of the EGFR inhibitory activity of the most active candidates—4a, 6b, 8b, 9a, and 9 d—was performed. Of them, compounds 9a and 8b demonstrated the highest IC₅₀ values, 0.08 and 0.15 µM, respectively, relative to the reference gefitinib (IC₅₀ = 0.04 µM). Subsequent mechanistic analysis of compound 9a revealed a notable 14.24-fold increase in overall apoptosis and a 28.92% cell cycle arrest at G2/M. Additionally, research on apoptosis demonstrated that it triggered the mitochondrial apoptotic pathway. In MCF-7 cells, it also led to an increase in ROS buildup. For the most powerful EGFR inhibitors, 9a and 8b, a molecular docking research was conducted, and all of the findings agreed with the biological findings.

New phthalazine-derived inhibitors for VEGFR-2 were synthesized for anticancer evaluations. Also, docking studies were performed to explore the suggested binding orientations of the novel derivatives inside the binding site of VEGFR-2. The achieved biological data were extremely interrelated to that of docking study. In specific, derivative 3f was the greatest effective compound against HepG2 and MCF-7 cancer cell lines with IC₅₀ = 0.17 ± 0.01 and 0.08 ± 0.01 µM individually. The six highly active derivatives 3b, 3e, 3f, 3g, 6a, and 6b were estimated for their VEGFR-2 inhibitory effects. Derivative 3f was the greatest effective compound which inhibited VEGFR-2 at IC₅₀ = 0.0557 ± 0.002 µM. The activities of 3f were assessed against MCF-7 cancer cells for apoptosis induction, cell cycle distribution, and growth inhibition. Compound 3f induced early apoptosis (21.44%) by more than 36 folds over the control (0.59%). The obtained results showed that compound 3f induced necrotic effect (6.03%) by more than threefolds over the control (1.75%). On the other hand, compound 3f improved the level of the pro-apoptotic protein; Bax by approximately fivefolds. Moreover, compound 3f noticeably decreased the levels of the anti-apoptotic proteins Bcl-2 by nearly fourfolds in comparison to the control. In addition, derivative 3f remarkably enhanced the Bax/Bcl2 ratio by nearly 18 folds, as compared to the control. Finally, our derivatives 3f, 3g, and 6b revealed good in silico considered ADMET profile in comparing to sorafenib.

Toll-like receptor 4 (TLR4) is an important mediator that activates bacterial inflammation through its signaling pathway. It binds lipopolysaccharide (LPS) in the presence of myeloid differentiation protein 2 (MD2) to dimerise the TLR4-MD2-LPS complex. The TLR4 mediated signaling pathway stimulates cytokine production in humans, initiating inflammatory responses. Overactivation of the TLR4 pathway can trigger binding of LPS to the TLR4-MD2 complex, which may lead to the development of several inflammatory disorders. Therefore, the TLR4-MD2 complex is a potential therapeutic target for the identification of new and effective anti-inflammatory agents. Various biologically active TLR4 and MD2 targeting natural and synthetic molecules are explored with anti-inflammatory activity in micromolar ranges. But no FDA-approved drugs are available in the market as of now, and some are discontinued in clinical trials due to drug resistance and severe side effects. In this review, we have assessed recent molecular advancements in TLR4-MD2 antagonists which are showing direct inhibition in lower micro and nanomolar levels. Along with it, protein informatics analysis of the binding pockets of wild type and mutated TLR4-MD2 proteins are also discussed here to give a new insight about the changes in physicochemical properties of the ligand binding area. We have also pointed out several important residues in three different sites of the large LPS binding pocket of TLR4-MD2 complex to understand probable binding affinity of small molecule inhibitors (SMIs). In addition, the present status of clinical trials for TLR4 antagonists is also reviewed. The current assessment will pave a future perspective to design different small molecules as a direct inhibitor of TLR4-MD2 complex for anti-inflammatory activities.

The development of anticancer drugs that target different organelles has received extensive attention due to the characteristics of cancer recurrence, metastasis, and drug resistance. The endoplasmic reticulum (ER) is an important structure within the cell that is primarily responsible for protein synthesis, folding, modification, and transport and plays a crucial role in cell function and health. ER stress activation induces cancer cell apoptosis. New anticancer drugs with different anticancer mechanisms and selectivity can be designed because of redox activity, composition diversity, and metal complexes structure regulation. Over the past few decades, dozens of metal complexes have killed cancer cells through ER stress, showing powerful tumor-suppressive effects. This review summarizes the progress of research on anticancer metallic drugs that induce ER stress over the past few years, which is expected to bring more breakthroughs in the field of medicine and life science.