Medicinal Chemistry最新文献

{"title":"Natural Mimetic 4,6-dihydroxyaurone Derivatives as Tyrosinase Inhibitors: Design, Synthesis, and Biological Evaluation.","authors":"Quoc-Thai Nguyen, Giao Quynh Tran, Huy Thanh Ta, Quang Dang Do, Quynh Xuan Vu, Bich-Loan T Phung, Thanh-Dao Tran, Khac-Minh Thai, Cam-Van T Vo","doi":"10.2174/0115734064371213250508115259","DOIUrl":"https://doi.org/10.2174/0115734064371213250508115259","url":null,"abstract":"<p><strong>Introduction: </strong>Tyrosinase, a key enzyme in melanin biosynthesis and food browning, has become an important target for inhibitor development.</p><p><strong>Aim: </strong>This study aimed to investigate the inhibitory potential of 4,6-dihydroxyaurone derivatives with varied ring B substituents on mushroom tyrosinase.</p><p><strong>Method: </strong>Twenty derivatives were designed and subjected to computational studies, revealing their potential to bind to the enzyme's active site and interact with key residues and copper ions.</p><p><strong>Result: </strong>In vitro UV-Vis spectrophotometry assays on these twenty synthesized aurones demonstrated that compound 5h, featuring a 3,4-dichlorophenyl group at ring B, exhibited the most potent inhibitory activity (IC₅₀ = 6.3 ± 0.3 μM) compared to kojic acid (IC₅₀ = 136.5 ± 11.5 μM). Further kinetic analysis and docking simulations suggested that 5h operated via a mixed inhibition mechanism with competitive and uncompetitive inhibitory constants of 21 μM and 68 μM, respectively.</p><p><strong>Conclusion: </strong>These findings highlight the promising potential of 4,6-dihydroxyaurone derivatives as potent tyrosinase inhibitors for applications in pharmaceuticals, cosmetics, and agriculture.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances in the Medicinal Chemistry of Cancer (Part 1).","authors":"Işıl Yıldırım","doi":"10.2174/0115734064404732250513074411","DOIUrl":"https://doi.org/10.2174/0115734064404732250513074411","url":null,"abstract":"","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovering the Cholinesterase Inhibitory Potential of Thiosemicarbazone Derivatives through <i>In vitro</i>, Molecular Docking, Kinetics, and Dynamics Studies.","authors":"Manel Essid, Aftab Alam, Ghulam Fareed, Sudais Rahman, Imtiaz Ahmad, Imen Zghab, Zainab Hassan Alnakhli, Abid Ali, Masroor Kamal, Momin Khan","doi":"10.2174/0115734064375028250427171931","DOIUrl":"https://doi.org/10.2174/0115734064375028250427171931","url":null,"abstract":"<p><strong>Background: </strong>The current study explored the cholinesterase inhibitory activities of some thiosemicarbazone derivatives bearing 2,4-dichloro phenylacetic acid scaffold.</p><p><strong>Objective: </strong>This study aimed to screen the synthesized derivatives for their <i>in vitro</i> acetylcholine and butyrylcholinesterase inhibition.</p><p><strong>Methods: </strong>These compounds were synthesized by refluxing 2,4-dichloro phenylacetic acid with sulfuric acid in ethanol to get the ester, which was further refluxed with thiosemicarbazide in ethanol to get the desired compound (2). Different benzaldehydes were treated with compound (2) in ethanol having a catalytic amount of acetic acid to get thiosemicarbazones.</p><p><strong>Results: </strong>In the series, seven compounds, including compounds 2c, 2a, 2b, 2d, 2g, 2e, and 2f, displayed excellent acetylcholinesterase inhibition activities in the range of IC₅₀ values from 41.51 ± 3.88 to 95.48 ± 0.70 μM, surpassing than the standard galantamine (IC₅₀ = 104.5 ± 1.20 μM). Also, compounds 2a, 2g, 2h, 2f, 2b, and 2d with IC₅₀ values ranging from 64.47 ± 2.74 to 80.62 ± 0.73 μM exhibited potent inhibition against butyrylcholinesterase enzyme, being similar to the standard galantamine (IC₅₀ = 156.8 ± 1.50 μM). The molecular docking investigation was performed to assess the binding affinity of the compounds with the active site of the enzyme. These compounds, along with the docked complexes, specifically AChE-compound 2a and BuChE-compound 2g, were chosen and subjected to 100-nanosecond molecular dynamics simulations. The simulations demonstrated strong stability of the ligands within the active pockets of AChE and BuChE enzymes.</p><p><strong>Conclusion: </strong>These derivatives exhibited superior acetylcholinesterase and butyrylcholinesterase inhibitory activities compared to galantamine, with molecular docking and dynamic simulations confirming their strong binding affinity with the active sites of the enzymes.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, Characterization, and Pharmacological Evaluation of Zn₄O(BDC)₃: Anticancer, Antidiabetic, and Drug Delivery Potential.","authors":"Sabir Khan, Muhammad Fazal Hameed, Imran Zafar, Rubina Bibi, Mohamed Mohany, Sadia Nazir, Mohammad Amjad Kamal, Muhammad Shafiq","doi":"10.2174/0115734064362203250222050726","DOIUrl":"https://doi.org/10.2174/0115734064362203250222050726","url":null,"abstract":"<p><strong>Introduction: </strong>This study presents a comprehensive exploration of the biomedical potential of the synthesized metal-organic framework Zn₄O(BDC)₃, focusing on its applications in cancer and diabetes treatment and its advanced drug delivery capabilities.</p><p><strong>Methods: </strong>The structural and physicochemical properties of Zn₄O(BDC)₃ were characterized using FTIR, TGA, ¹H NMR, PXRD, and elemental analysis, revealing its exceptional stability and coordination properties. Molecular docking, molecular dynamics simulations (100 ns), and MM-GBSA calculations were performed to assess binding affinities and stability.</p><p><strong>Results: </strong>The interactions of Zn₄O(BDC)₃ with salmon sperm DNA (SSDNA) and bovine serum albumin (BSA) demonstrated significant anticancer potential, evidenced by binding constant values of 6.0 × 10⁶M^-1 and Gibbs free energy changes of -17.93 and -19.61 kcal/mol, respectively, highlighting its ability to suppress tumor cell proliferation. With doxorubicin (DOX) loading and reloading efficiencies of 88% and 87.5%, Zn₄O(BDC)₃ exhibited superior drug delivery capabilities. The anti-diabetic potential was validated by the formation of human insulin (HI) hexamers with ΔG values of 0.8 ± 0.1 and a significant decrease in absorption intensity (5.8 to 0.05 at 250 nm). Molecular docking studies revealed moderate to high binding affinities (-10.0 to -5.3 kcal/mol) with biomolecular targets, supported by molecular dynamics simulations over 100 ns and MM-GBSA calculations indicating robust stability (ΔG = -33.31 kcal/mol).</p><p><strong>Conclusion: </strong>These <i>in-silico</i> and <i>in-vitro</i> analyses underscore the significant pharmacological promise of Zn₄O(BDC)₃ as a multifunctional agent for anticancer, antidiabetic, and drug delivery applications.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Screening of Novel Inhibitors Targeting the Non-ATP-binding Domain of <i>Staphylococcus aureus</i> SecA1.","authors":"Yan Liu, Qing Su, Zonglin Wang, Peiyao Liu, Jinjin Hong, Hyuk-Kyu Seoh, Xu Jia, Sen-Fang Sui, Phang-Cheng Tai, Xinhe Huang","doi":"10.2174/0115734064370398250426162503","DOIUrl":"https://doi.org/10.2174/0115734064370398250426162503","url":null,"abstract":"<p><strong>Objective: </strong><i>Staphylococcus aureus (S. aureus)</i> has been one of the pathogenic bacteria for clinical infections, and there is an urgent need for the development of novel anti-<i>S. aureus</i> drugs. SecA is a conserved and essential protein in bacteria and is considered as an ideal target for development. Current screening of inhibitors against SecA has focused on the ATP-binding structural domain, which increases the risk of drug side effects, so a novel screening strategy based on the non-ATP-binding structural domain was chosen in this paper.</p><p><strong>Methods: </strong>A three-dimensional structural model of <i>S. aureus</i> SecA1N75 was constructed, and molecular docking was utilized to screen small molecules with strong interactions with the non- ATP binding domains from a compound library, and four candidate compounds were finally targeted. Molecular dynamics simulations of the candidate molecules were performed to evaluate their drug potential.</p><p><strong>Results: </strong>The four candidate compounds formed stable interactions with key residues of the SecA binding pocket. Molecular dynamics simulations further showed that the candidate molecules bound to the receptor in a stable conformation with nM-level inhibition constants, displaying potent SecA inhibitory activity. It lays the foundation of a lead compound for the development of antimicrobial drugs targeting SecA.</p><p><strong>Conclusion: </strong>In this thesis, an inhibitor screening strategy based on non-ATP binding structural domains was successfully constructed, which breaks through the limitations of traditional methods to screen candidate molecules with high activity and low risk of potential side effects, and provides an innovative solution to meet the challenge of <i>S. aureus</i> drug resistance.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibitors of Phosphatidylinositol-specific Phospholipase C with <i>Myo</i>-inositol Scaffold.","authors":"Christian Bierkamp, Walburga Hanekamp, Christoph Arenz, Matthias Lehr","doi":"10.2174/0115734064384345250415073648","DOIUrl":"https://doi.org/10.2174/0115734064384345250415073648","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes catalyze the conversion of phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol- 1,4,5-trisphosphate, both of which play crucial roles in regulating biochemical processes. Despite the wellestablished link between elevated PI-PLC activity and pathophysiological conditions, no PI-PLC inhibitors are currently in clinical development. Moreover, existing inhibitors demonstrate only limited potency.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Due to the structural similarity with known inhibitors with a myo-inositol backbone, DL-1-Ododecylsulfonyl- myo-inositol-3,5-bisphosphate, designated as acid sphingomyelinase inhibitor, and derivatives thereof should be tested for inhibition of PI-PLC activity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The newly synthesized compounds were evaluated for their ability to inhibit PI-PLC activity in porcine platelet lysate and porcine brain homogenate, as well as their inhibitory potency against the recombinant isoenzymes PLCγ1 and PLCγ2. The assay measured the release of diacylglycerol from L-α- phosphatidylinositol using HPLC coupled with MS detection. Furthermore, the specificity of selected compounds was assessed by determining their inhibitory potency against other surface-active enzymes through HPLC-based assays.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;It was found that DL-1-O-dodecylsulfonyl-myo-inositol-3,5-bisphosphate inhibits PI-PLC activity at micromolar concentrations. However, its maximum achievable inhibitory effect was limited to approximately 70%. Through structural modifications, inhibitors were developed that led to near complete inhibition of PIPLC activity. The study also revealed that the alleged PI-PLC inhibitor U73122, still frequently cited in the literature to demonstrate PI-PLC involvement in biochemical processes, is unsuitable for this purpose. Consistent with observations by others, its inhibitory activity in bionucleophile-containing cell or tissue preparations was found to be significantly lower than its activity against purified PI-PLC enzymes. Additionally, U73122 was shown to inhibit other enzymes, such as cytosolic phospholipase A2α, fatty acid amide hydrolase, and monoacylglycerol lipase, which, like PI-PLC, metabolize lipophilic substrates. In contrast, the newly developed myo-inositol derivatives exhibited reduced sensitivity to bionucleophiles and significantly improved selectivity against the tested surface-active enzymes compared to U73122.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;New compounds exhibiting significant inhibitory activity against PI-PLC have been identified. The findings could prove valuable in the development of clinically applicable PI-PLC inhibitors, particularly for the treatment of cancer. Additionally, the myo-inositol derivatives developed demonstrated greater suitability for studying PI-PLC's role in physiological processes in tissue homogenates compared ","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, and Biological Evaluation of a Novel Series of Thiazolidinediones as Dual GSK-3ß and Tau Aggregation Inhibitors.","authors":"Zahra Abdollahi, Khalil Abnous, Mohamad Reza Kalani, Seyed Mohammad Taghdisi, Somaieh Soltani, Mojgan Nejabat, Farzin Hadizadeh","doi":"10.2174/0115734064369119250413021648","DOIUrl":"https://doi.org/10.2174/0115734064369119250413021648","url":null,"abstract":"<p><strong>Introduction: </strong>Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase that is involved in the synthesis of glycogen. Among the inhibitors, thiazolidinediones (TZDs) can specifically bind to GSK-3ß. They act non-competitively with ATP, and as a result, they are very specific and have fewer side effects. In this research, new TZDs were designed and synthesized, and then their inhibitory effects on GSK-3β enzyme and tau aggregation were investigated.</p><p><strong>Material and methods: </strong>The structure of the compounds was confirmed using 1H-NMR, 13CNMR, and LC-MASS. The inhibitory activities of the compounds 5a-p, against GSK-3ß were evaluated using Z'-LYTE technique, and the IC50 values were determined.</p><p><strong>Results: </strong>Compound 5l (R1 = Me, R2 = 4-F-benzyl, R3 = butyl) with IC50 of 16.1 μM exhibited the most potent inhibition. Also, the binding with tau protein and their inhibitory effects on the accumulation of recombinant human tau protein (1N4R, htau34) were evaluated using the Surface Plasmon Response (SPR) method. In this study also the impact of TZDs on tau aggregation using the Thioflavin T (ThT) assay was investigated. PC12 cells viability study confirmed the neuroprotective effects of compounds against tau aggregates. MD simulation studies showed the interaction of 5l with the active site of GSK-3b (PDB ID: 2OW3) and also its destructive effect on tau aggregate (PDB ID: 5O3L) was studied.</p><p><strong>Conclusion: </strong>Overall, the study identified three promising TZDs with potential as inhibitors of GSK-3β and tau proteins, highlighting compound 5l as particularly effective in stabilizing GSK- 3β and disrupting tau aggregation.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin-Based Virtual Screening Identifies Inhibitors of SARS-CoV-2 Spike Protein and ACE2 Receptor Binding.","authors":"Timoteo Delgado-Maldonado, Luis D Gonzalez-Morales, Gilberto Vargas-Salas, Guadalupe Rojas-Verde, Eyra Ortíz-Pérez, Alma D Paz-Gonzalez, Gildardo Rivera","doi":"10.2174/0115734064371154250414064157","DOIUrl":"https://doi.org/10.2174/0115734064371154250414064157","url":null,"abstract":"<p><strong>Background: </strong>To date, COVID-19 has caused over 772 million cases, with approximately 7 million deaths, according to the World Health Organization. Therefore, there is a need to develop new drugs to address the challenges posed by this disease.</p><p><strong>Objective: </strong>To propose new antiviral agents based on the natural product curcumin as potential protein-protein interaction inhibitors between the SARS-CoV-2 spike receptor binding domain (RBD) and the ACE2 receptor.</p><p><strong>Methods: </strong>A curcumin-based virtual screening was performed (Tanimoto coefficient= 0.9), and molecular docking analysis were carried out using the RBD as a receptor. Molecular dynamics (MD) using GROMACS were conducted for 120 ns. The SwissADME server was used to predict pharmacokinetics. To validate predictions, an in vitro enzyme assay measuring the relative inhibition of the interaction between the RBD and the ACE2 receptor was performed.</p><p><strong>Results: </strong>More than 1300 ligands were evaluated through molecular docking. The docking results were analyzed, and the ligands were classified according to their score and profile of interactions with residues of the RBD of the SARS-CoV-2 S glycoprotein. The top ten with the best scores and interactions were selected to verify the commercial availability. The lead compound Cu-1 demonstrated significant interactions with the RBD and stability in MD simulations, was acquired and evaluated in vitro. Compound Cu-1 inhibited 36 ± 0.7 % the interaction between the SARSCoV- 2 spike and the ACE2 receptor. In addition, Cu-1 was shown to have an acceptable druglikeness and pharmacokinetic profile.</p><p><strong>Conclusion: </strong>Curcumin provides a scaffold for identifying novel compounds with potential antiviral activity. Further studies on compound Cu-1 could yield on optimizing its structure to increase activity targeting the RBD of the S glycoprotein.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scaffold Hopping and Optimization of Thiazole Hybrids as Selective PIN1 Inhibitors: A Computational Study.","authors":"Meeramol C Chellappan, Soumya Vasu, Shriraam Mahadevan, M K Kathiravan, J Saravanan, Soniya Naik, Knolin K Thachil","doi":"10.2174/0115734064376657250416071044","DOIUrl":"https://doi.org/10.2174/0115734064376657250416071044","url":null,"abstract":"<p><strong>Background: </strong>Protein Interacting with NIMA1 (PIN1) is a distinct enzyme, known as a peptidyl-prolyl cis-trans isomerase (PPIase), which catalyzes the cis-trans isomerization of amide bonds in proteins containing phosphoserine/threonine-proline (pSer/Thr-Pro) motifs, presenting a unique therapeutic opportunity for addressing multiple disorders.</p><p><strong>Methods: </strong>A series of 140 thiazole compounds were created using the shape similarity technique with the intention of discovering effective PIN1 inhibitors with a new scaffold. The designed compounds were docked into the enzyme's ATP binding site, and the binding free energies for all docked conformations were calculated. The compounds were evaluated for their ADMET and drug-likeness properties. Following the identification of top candidates, molecular dynamics simulations were conducted to investigate the binding dynamics of the highest-scoring compound.</p><p><strong>Results: </strong>Based on computational findings, sixteen compounds were identified as potential PIN1 inhibitors. Among the sixteen compounds, four (S8Ba, S8Bb, S8Bd, and S8Bd) exhibited the most favorable ADMET profiles and robust interactions with key PIN1 residues. Molecular dynamics simulations confirmed that S8Ba and S8Bd exhibited the most promising activity over 100ns.</p><p><strong>Conclusion: </strong>The results corroborated the docking outcomes, validating the selected hits as potential PIN1 inhibitors. This breakthrough could influence the development of therapeutic leads for combating diabetes, cancer, and Alzheimer's disease.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reducing Cabozantinib Toxicity in Renal Cell Carcinoma Treatment through Structural Modifications.","authors":"Jiaxiang Guo, Xiaotao Yin, Yongliang Lu, Yu Yang","doi":"10.2174/0115734064374511250411104320","DOIUrl":"https://doi.org/10.2174/0115734064374511250411104320","url":null,"abstract":"<p><strong>Background and objectives: </strong>Cabozantinib, a Tyrosine Kinase Inhibitor (TKI), is widely used in Renal Cell Carcinoma (RCC) therapy but often causes serious side effects such as myelosuppression, immunosuppression, and angiopathy. This study aims to identify key protein targets responsible for the therapeutic efficacy and adverse reactions of cabozantinib and to explore structural modifications to reduce toxicity while preserving efficacy.</p><p><strong>Methods: </strong>A non-randomized computational approach was employed, screening 400 potential protein targets using SwissTargetPrediction and ChemBL databases. Molecular docking and Structure-Activity Relationship (SAR) analysis were performed to assess interactions between cabozantinib and identified targets, focusing on structural elements contributing to toxicity.</p><p><strong>Results: </strong>Three primary proteins were identified as responsible for the anti-tumor effects of cabozantinib, while three others were linked to its side effects. Docking analysis revealed that the methoxyphenyl group in cabozantinib formed undesirable hydrogen bonds with toxicity-related proteins. Modulating these off-target interactions by minimizing hydrogen bonding in this region could significantly reduce adverse effects.</p><p><strong>Conclusion: </strong>These findings provide structural insights into cabozantinib's dual effects and suggest optimization strategies for TKI design, offering a pathway toward safer and more effective RCC treatments.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}