Letters in Drug Design & Discovery最新文献

{"title":"Flavonoids as Pyruvate Kinase M2 Inhibitor: An in silico Analysis","authors":"Raghav Mishra, Sparsh Kaushal, Isha Mishra","doi":"10.2174/1570180820666230816090541","DOIUrl":"https://doi.org/10.2174/1570180820666230816090541","url":null,"abstract":"\u0000\u0000The prevalence of cancer in developing nations is a significant issue of concern.\u0000As a result of diverse global influences, this condition has surpassed coronary ailments to become the\u0000foremost cause of mortality. The role of PKM2 (Muscle Pyruvate Kinase 2) has garnered significant interest in the quest for agents in cancer progression. Flavonoids exhibit promise as a framework for the\u0000advancement of chemotherapeutic agents targeting cancer.\u0000\u0000\u0000\u0000The principal aim of the present in silico investigation was to ascertain flavonoids as potential\u0000anticancer agents capable of inhibiting the PKM2 enzyme.\u0000\u0000\u0000\u0000The preferred ligand molecules were docked to the human PKM2 enzyme using a computational molecular docking simulation technique to determine their affinity for the same enzyme. The molecular\u0000docking simulation was carried out using the AutoDock Vina software.\u0000\u0000\u0000\u0000The chosen flavonoid docked well with the PKM2 enzyme, suggesting it may stimulate autophagy, hence acting as an anticancer agent.\u0000\u0000\u0000\u0000In in silico studies, the chosen flavonoids showed a strong binding affinity, indicating that\u0000all of them impede the human PKM2 enzyme and have the potential to be used as cancer treatment alternatives.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90234219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, Molecular Docking Studies and Biological Evaluation of N-(α-benzamido cinnamoyl) Piperonal Hydrazones","authors":"G. Rajitha, K. Saritha, T. Sarala Devi, M. Vidya Rani, K. Sudheer Kumar, A. Umamaheswari","doi":"10.2174/1570180820666230816091339","DOIUrl":"https://doi.org/10.2174/1570180820666230816091339","url":null,"abstract":"\u0000\u0000Nowadays, inflammation is recognized as the underlying cause of a number of diseases, but NSAIDs are the first drug of choice, having several side effects. Additionally, excessive cellular oxidative stress is often considered a major contributor to pathophysiological conditions, the development of cancer, and other diseases. Antimicrobial resistance is a global concern, hence, there is a critical need for the development of novel therapeutic agents to fight the emergence and increasing prevalence of resistant pathogens. This creates an initiation to introduce new molecules which act as efficient therapeutic agents with diminished side effects.\u0000\u0000\u0000\u0000As a part of our search for newer agents with enhanced activity profiles, it was planned to synthesize novel 2- (benzamido)-N-((benzo[d][1,3]dioxol-4-yl)methylene)-3-(substituted phenyl) acrylohydrazides and to investigate them for antiinflammatory, antioxidant, cytotoxic, antimicrobial activities. Furthermore, in silico studies were performed for title compounds to predict molecular properties, bioavailability, drug-likeness, and bioactivity scores, molecular docking studies were also performed against biological targets.\u0000\u0000\u0000\u0000The title compounds 1-14 were synthesized by nucleophilic addition of piperonal in ethanol, few drops of acetic acid to the intermediate 2-(benzamido)-3-(aryl)acrylohydrazides. The title compounds were tested for their antiinflammatory activity by in vivo carrageenan-induced rat paw edema method, in vitro COX-2 inhibition assay; in vitro cytotoxic activity evaluation by MTT assay; antioxidant activity by Lipid peroxidation, DPPH assay, Nitric Oxide scavenging assay and Hydrogen peroxide scavenging assay; and antimicrobial activity by cup plate method. Physicochemical properties and bioactive scores of title compounds were evaluated by in silico studies. Molecular docking studies were carried out for the title compounds against COX-2 (PDB: 5F19) and EGFR (PDB:1XKK).\u0000\u0000\u0000\u0000Among the series, 4-Hydroxy-3,5-dimethoxy derivative (5) displayed good anti-inflammatory and antioxidant activities; Vanillinyl derivative (4) displayed good cytotoxicity and antimicrobial activity when compared to that of the respective standards. Compounds 5 & 4 also exhibited good docking scores with COX-2 and EGFR, respectively. All title compounds obeyed Lipinski’s rule of five and also exhibited acceptable molecular properties, drug-likeness properties, and moderate to good bioactivity scores in in silico studies.\u0000\u0000\u0000\u0000The study suggested that the title compounds showed notable pharmacological properties, could emerge as lead compounds, and be further explored as promising therapeutic agents.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77381352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flavonoids in Astragali Radix Functions as Regulators of CDK2, VEGFA and MYC in Osteoporosis and Type 1 Diabetes Mellitus","authors":"X. Qu, Xiangding Chen, Zimeng Liu, Xuemei Zuo, Yisheng Cai, Yuyang Zuo, Keqiang Ma, Shuang Wu","doi":"10.2174/1570180820666230811150017","DOIUrl":"https://doi.org/10.2174/1570180820666230811150017","url":null,"abstract":"\u0000\u0000People with type 1 diabetes mellitus (T1DM) are significantly more likely to have osteoporosis (OP). Astragali Radix is a Chinese herbal medicine containing various active ingredients, and several clinical trials have been reported to use it to treat OP and T1DM, respectively.\u0000\u0000\u0000\u0000To evaluate the targets and potential mechanisms of Astragali Radix administration on OP and T1DM.\u0000\u0000\u0000\u0000The targets of Astragali Radix were identified using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The OP and T1DM datasets were downloaded from the Gene Expression Omnibus (GEO) database. The weighted gene correlation network analysis (WGCNA) method was used to identify the co-expression genes associated with OP and T1DM. In addition, the common gene targets of OP and T1DM were screened using two public databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R tool. After the validation of key genes, molecular docking was performed to visualize small molecule-protein interactions.\u0000\u0000\u0000\u0000The compound target network mainly contained 17 compounds and 147 corresponding targets. There were 561 GO items and 154 signaling pathways in KEGG, mainly including the AGE-RAGE signaling pathway in diabetic complications and osteoclast differentiation. The results of molecular docking showed that flavonoids were the top compound of Astragali Radix, which had a high affinity with CDK2, VEGFA, and MYC.\u0000\u0000\u0000\u0000Flavonoids in Astragali Radix may regulate multiple signaling pathways through MYC, CDK2, and VEGFA, which may play a therapeutic role in OP and T1DM.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74965911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural phytochemicals, phenformin, and docosahexaenoic acid (DHA) as Novel Inhibitors of leukotriene B4 and ACE2 receptors, a Therapeutic Strategy for targeting COVID-19 Cell Entry and Cytokine Storm. (An In-silico Approach)","authors":"Abdullah Haikal, A. Ahmed, I. Rahman, Hazar S Alharbi, E. S. Radwan, A. S. Abouzied, Ngoc NH Pham, Mohammad Shahbaz Khan, W. A. Eltayb, N. Khalifa, Tomasz M. Karpinsk, Weam M A Khojali, Eman I. Anwar, Israa. M. Shamkh, M. Elkazzaz","doi":"10.2174/1570180820666230810144401","DOIUrl":"https://doi.org/10.2174/1570180820666230810144401","url":null,"abstract":"\u0000\u0000Cytokine storm syndrome (CSS) is a life-threatening consequence of inflammatory, immunological illnesses; it can also occur with COVID-19 infection. CSS is characterized by a disruption in cytokine synthesis, including regula-tory, pro-inflammatory, and anti-inflammatory cytokines, resulting in pathologic stimulation of innate in addition to adaptive (Th17 and Th1 mediated) response. In the pathophysiology of CSS, leukotriene could play a key role. The sig-nificant role of leukotriene in COVID-19 pathogenesis was established in a wide variety of research, which reported that the plasma concentration of leukotriene was raised in COVID-19 patients with severe symptoms. COVID-19 spike pro-tein binding to angiotensin-converting enzyme 2 (ACE2), the virus’s cellular receptor, causes a cascade of molecular processes that could result in hyperinflammation, which may lead to cytokine storm. Therefore, the development of new natural therapies and repurposing some drugs such as Phenformin and docosahexaenoic acid that could compete with COVID-19 for ACE2 binding activity may possibly help COVID-19 patients avoid a cytokine storm and save their lives by preventing SARS-CoV-2 RBD attachment to ACE2.\u0000\u0000\u0000\u0000Herein, we made docking-based screening for some natural phytochemicals and drugs that could be repur-posed according to our findings to counter COVID-19 cell entry and inhibit the hyperactivation of leukotriene B4.\u0000\u0000\u0000\u0000Our results revealed that phytochemicals including (bromelain, epigallocatechin gallate, isovitexin, luteolin, metformin, quercetin, and vitexin) showed high binding affinities with best interactions with the active sites of leukotri-ene B4. The binding affinities of these phytochemicals were (-7.2, -8.3, -7.2, -5.0, -4.11, -5.1 and -7.7kcal/mol), respectively. In addition, Phenformin and Docosahexaenoic acid (DHA) showed a high binding affinity with the best interactions with the active sites of ACE2. The binding affinity of Phenformin and docosahexaenoic acid (DHA) with ACE 2 was (-7.2) and (-6.3), respectively.\u0000\u0000\u0000\u0000As a result, these compounds could be used as a new therapy to prevent COVID-19 cell entrance and associ-ated inflammatory consequences.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87992093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and synthesis of gefitinib derivatives as potential drugs for cancer treatment: antiproliferative activity, molecular docking, and ADMET prediction","authors":"Yunlong Lu, Xiaoyan Ma, Min Shan","doi":"10.2174/1570180820666230810164118","DOIUrl":"https://doi.org/10.2174/1570180820666230810164118","url":null,"abstract":"\u0000\u0000Non-small cell lung cancer is one of the most common cancers worldwide, and targeted chemotherapy has become a kind of the main treatment. Gefitinib, the most widely studied targeted agent in non-small cell lung cancer, is an orally active tyrosine kinase inhibitor. However, gefitinib inevitably generates acquired drug resistance, leading to treatment failure.\u0000\u0000\u0000\u0000A new class of compounds containing 4-anilinoquinazoline lead structure was designed and synthesized by modifying the structure of gefitinib. These compounds are expected to exert better anticancer activity and better binding to the EGFR-TK domain, enrich the structure of 4-anilinoquinazoline derivatives and inspire further structural modifications.\u0000\u0000\u0000\u0000The antiproliferative activity of nine derivatives was determined in three cancer cell lines (A549, PC9, and HepG2) using the MTT method. The ADMET profile of all compounds was predicted, and the binding affinity of the compounds (5 and 6) to EGFR was predicted by Schrödinger. In addition, the effect of these compounds (3-6) in inducing apoptosis in HepG2 cells was also studied.\u0000\u0000\u0000\u0000Four (3, 5, 6 and 9) of the newly synthesized derivatives exhibited superior antiproliferative activity against A549 to gefitinib (IC50 = 12.64 ± 3.59 μM), with compound 5 having the best activity (IC50 = 7.39 ± 1.24 μM). Moreover, the ability of compounds (3-6) to induce HepG2 cell apoptosis was significantly better than that of gefitinib.\u0000\u0000\u0000\u0000Nine structures (compounds 2-10) were synthesized and characterized, and compound 5 had the best antiproliferative activity. Compound 3 possessed the best ability to induce HepG2 apoptosis. Also, ADMET calculations were performed in silico, and the results revealed that compound 3 has more suitable characteristics as a potential drug candidate.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90196899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent review on 1,3-thiazole derivatives as therapeutic targeted for anticancer activity","authors":"Shweta Mishra, Adarsh Sahu","doi":"10.2174/1570180820666230809153027","DOIUrl":"https://doi.org/10.2174/1570180820666230809153027","url":null,"abstract":"\u0000\u0000In the past two decades, targeted cancer therapy has emerged as a novel class of anticancer therapeutics besides traditional chemotherapy, surgery, and radiotherapy. There is an extensive variety of anticancer drugs in the market, and several compounds are in various stages of clinical trials. Many studies indicate that these cytotoxic molecules are also associated with various types of toxicity and contrary side effects; thus, researchers all over the world are working to develop more effective and safer anticancer drugs. 1,3-thiazole derivatives have recently been identified as a novel class of cancer chemotherapeutic agents with promising activity against various tumors. In this review, we have systematically summarized and highlighted the latest developments in 1,3-thiazole derivative for anticancer activity.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77856633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insight on the Pharmacological Potential and Bio-active Components of Ginger","authors":"Ayushi Sethiya, Pankaj Teli, Dinesh Kumar Agarwal, S. Agarwal","doi":"10.2174/1570180820666230807152019","DOIUrl":"https://doi.org/10.2174/1570180820666230807152019","url":null,"abstract":"\u0000\u0000Ginger is a very renowned herbaceous plant that has been extensively used as a flavoring agent and herbal medicine for decades. It possesses a plethora of pharmacological properties, including anti-inflammatory, anti-oxidant, antimicrobial, anti-diabetic, anti-tumor, anti-viral, anti-Alzheimer, analgesic, cardio-vascular, etc. In this review, a comprehensive summary of the pharmacological potentials of ginger and its bioactive components is described. Their mechanisms of action against different diseases and targets are also discussed, which can lay the foundation for their medical applications.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77109910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Solubility, the Main Concern for Poorly Water-soluble Drugs: Techniques and Alternatives","authors":"Komal Singh, P. Singh, Amanda Frank, Saahil Arora, Rajiv Sharma, Neha Bajwa","doi":"10.2174/1570180820666230807163632","DOIUrl":"https://doi.org/10.2174/1570180820666230807163632","url":null,"abstract":"\u0000\u0000The most important variable that affects a drug's bioavailability is its aqueous solubility. One of the biggest issues facing the pharmaceutical business is improving water solubility, which is the key to improving therapeutic efficacy. During the first screening procedure, over 50% of recently created medications are discovered to be insoluble or weakly soluble. The solubility of the medicine can be increased using a variety of techniques. The method entails both chemical and physical drug modifications. Any medicine that is absorbed must be present at the absorption site in the form of a solution. Poorly soluble medications can be made more soluble using a variety of approaches, like physical and chemical alterations to the drug and other strategies. Using a surfactant, complexation, and so on are examples of solid dispersion. The choice of a solubility-improving technology is influenced by pharmacological properties, absorption sites, and the requirements for the dosage form. In order to serve as a quick reference, this study attempted to gather information on various solubility improvement methods and organize it systematically.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89536638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic and Pharmacological Expedition of Pyrazolo[1,5-a]pyridine: A Comprehensive Review","authors":"N. Agrawal, Dimple Bansal, V. Gautam","doi":"10.2174/1570180820666230803101948","DOIUrl":"https://doi.org/10.2174/1570180820666230803101948","url":null,"abstract":"\u0000\u0000Fused nitrogen-containing heterocyclic compounds have been identified to display a prominent role in medicinal chemistry, biochemistry, and other streams of science. Countless derivatives of pyrazolo[1,5-a] pyridine have been investigated by researchers for their distinct pharmacological characterization. In this article, we have revealed and arranged the various routes of synthesis and\u0000therapeutic activities such as dopamine binding affinity, kinase inhibitory activity, and PDE inhibitors of\u0000pyrazolo[1,5-a]pyridine-containing compounds which have been explored till now. The remarkable outcomes obtained via in vitro as well as in vivo profile screening of this moiety and its derivatives lead this\u0000scaffold to be recognized to a greater extent and examined further for better results.\u0000\u0000\u0000\u0000This review will give medicinal chemists a flying-bird eye catch view of pyrazolo[1,5-a]\u0000pyridine derivatives which will help them to design and synthesize potential compounds bearing this moiety.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87066810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Novel PLK1 Inhibitors Based on Computational Studies of 2,4-Diarylaminopyrimidine Derivatives","authors":"Honghao Yang, Yilan Zhao, Xiaojiao Zheng, X. Ju, Fengshou Wu, Xiao-Fei Luo, Qi Sun, Genyan Liu","doi":"10.2174/1570180820666230801114905","DOIUrl":"https://doi.org/10.2174/1570180820666230801114905","url":null,"abstract":"\u0000\u0000Polo-like kinase 1 (PLK1) is an important target for anti-cancer drugs. A series of novel 2,4-diarylaminopyrimidine derivatives (DAPDs) as PLK1 inhibitors (PLKIs) with remarkable activities have been reported recently.\u0000\u0000\u0000\u0000A systemically computational study was performed on these DAPDs, including three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, and molecular dynamics (MD) simulation.\u0000\u0000\u0000\u0000The constructed 3D-QSAR models exhibited reliable predictability with satisfactory validation parameters. The dockings revealed the binding modes of DAPDs in PLK1 protein, and two key residue, Cys133 and Phe183, could interact with DAPDs by hydrogen bonds and π-π stacking, which might be significant for the activity of these PLKIs. Eight compounds with higher predicted activity than the most active DAPD-compounds (16) were designed based on the 3D-QSAR models. These newly designed compounds also exhibited higher docking scores than compound 16 in the binding pocket of PLK1. The ADME predictions and MD simulations further indicated that two hit compounds with reasonable pharmacokinetics properties could stably bind with PLK1 and have the potential to become novel PLKIs.\u0000\u0000\u0000\u0000Two newly designed compounds might have the potential to be novel PLKIs. These results might provide important information for the design and development of novel PLKIs.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90603761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}