Letters in Drug Design & Discovery最新文献

{"title":"Predicting the Pharmacological Targets of Astragalus membranaceus against Hypertensive Nephropathy","authors":"Ningxin Zhang, Chen Guan, Lingyu Xu, Zengying Liu, Chenyu Li, Quandong Bu, Xuefei Shen, Yan Xu","doi":"10.2174/0115701808285471240216040105","DOIUrl":"https://doi.org/10.2174/0115701808285471240216040105","url":null,"abstract":"Objective: Hypertension is one of the main causes of chronic kidney disease. Astragalus membranaceus (AM), an important traditional Chinese medicine for treating hypertensive nephropathy, has a complex composition that makes it challenging to explore its mechanism of action and limits its clinical application. This study aims to investigate the underlying mechanism of AM in treating hypertensive nephropathy. Methods: We retrieved all the compound data of AM from the Traditional Chinese Medicine Systems Pharmacology database and screened out the active compounds and their target proteins. Then, a network of candidate compounds and target compounds of AM was constructed using Cytoscape software. Furthermore, hypertensive nephropathy-related genes from the DisGeNET and GeneCards databases were intersected with AM target proteins and hypertensive nephropathy-related genes to determine the potential targets of AM in treating hypertensive nephropathy. Finally, after performing Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, we conducted molecular docking to verify the interaction between the main active ingredients of AM and the core targets. Results: A total of 87 effective components of AM were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. According to the network of active compounds and their target proteins, 18 of the 20 effective compounds in AM could act on 210 proteins. Taking the intersection of 274 hypertensive nephropathy-related genes and AM target proteins, 49 potential targets of AM in treating hypertensive nephropathy were identified. Using the median degree value, we determined 25 core targets of AM in treating hypertensive nephropathy. GO enrichment analysis showed that the biological processes of AM on hypertensive nephropathy mainly focused on the inflammatory response, hypoxia response, angiogenesis, cell proliferation, and cell migration. KEGG pathway enrichment analysis mainly involved cancer pathways, the AGE-RAGE signaling pathway in diabetic complications, blood flow shear stress, and atherosclerosis. Molecular docking results showed that quercetin, kaempferol, and 7-O-methylisomucronulatol had strong binding activity with several target proteins and may exert protective effects by stabilizing the interaction between molecules through the intermolecular forces of hydrogen bonds. Conclusion: This study reveals the targets of AM in treating hypertensive nephropathy using network pharmacology and molecular docking, providing new clues for developing novel drugs for hypertensive nephropathy and basic research development.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140018207","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":"Development of Potential Antidiabetic Agents Using 2D and 3D QSAR, Molecular Docking and ADME Properties In-silico Studies of α-Amylase Inhibitors","authors":"Kalusing S. Padvi, Aniket P. Sarkate, Shashikant V. Bhandari, Mahadevi V. Kendre","doi":"10.2174/0115701808279839240206123454","DOIUrl":"https://doi.org/10.2174/0115701808279839240206123454","url":null,"abstract":"Background: A series of 2-arylbenzimidazole derivatives were designed and developed as antidiabetic drugs using 2D and 3D QSAR, molecular docking and ADME studies. background: A series of 2-arylbenzimidazole derivatives were designed and developed as antidiabetic drugs using 2D and 3D QSAR, molecular docking and ADME studies. Methods: All molecular modeling studies were performed using Molecular Design Suite V-Life MDS software. New chemical entities (NCEs) were designed based on the results of 2D and 3D QSAR studies. Docking studies were performed with the designed NCEs in PDB: 5E0F and the results were compared with the receptor ligand. According to the ADME results, all the proposed compounds have good oral absorption, correct molecular weight, QPlogPo/w. All units show oral absorption above 80%, it is considered well absorbed. All the proposed units show satisfactory results in the area. This indicated that these NCEs have little or no chance of failure in the final stages of the drug development process. Results: The 2D QSAR results showed that the descriptor k2alpha, T_T_N_5, IodinesCount and BrominesCount play the most important role in determining the inhibitory activity of α-amylase. Although 3D QSAR showed that, the q2 and Pred_r2 values of the model (SA kNN MFA model) were 0.7476 and 0.6932. The G score of the proposed compound numbers mol-1, mol-2, mol-3, mol- 4, mol-5, mol-6, mol-7 and mol-8 are better compared to the standards, indicating that the proposed compounds have good binding properties affinity to bind to α-amylase. Conclusion: These investigations have produced statistically significant and exceptionally reliable 2D and 3D Quantitative Structure-Activity Relationship (QSAR) models for antidiabetic medications, particularly α-amylase inhibitors. Furthermore, docking experiments involving the α-amylase enzyme have revealed that the binding energies of most Novel Chemical Entities (NCEs) are comparable to those of the established standards. Docking studies with α-amylase enzyme showed that most NCEs have binding energies comparable to the standard.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140010057","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":"Do Anticancer Medicinal Compounds have DNMT1 Regulating Activity: An In silico Investigation","authors":"Fahad Hassan Shah, Song Ja Kim","doi":"10.2174/0115701808265886230921115023","DOIUrl":"https://doi.org/10.2174/0115701808265886230921115023","url":null,"abstract":"Background:: DNA methyltransferases (DNMTs) are a group of epigenetic enzymes implicated in regulating gene expression in actively dividing cells. Among these enzymes, DNMT1 plays a leading role in causing increased DNA methylation of tumor suppressors and other genes in cancer cells. This methylation event disrupts the cell cycle regulating genes, allowing an uninterrupted proliferation of cancer cells, and stimulating the inhibition of the degradation of proteins and aberrant transcription activation. Cytosine analog drugs have been shown to reduce DNA methylation but provoke the expression of other prometastatic genes. On the other hand, medicinal compounds act similarly to cytosine analogs by reducing the expression and activity of DNMT1, as reported in some in vitro cancer studies. However, it remains a mystery what those promising medicinal compounds are that show such activity. Objectives:: The objective of this study was to screen medicinal compounds that reduce the expression and interact with the active site residues of DNMT1. Methods:: To analyze medicinal compounds against DNMT1, two in silico tools were employed: DIGEP-pred and IGEMDOCK to discover and identify 98 lead medicinal compounds having anticancer potential, capable of regulating DNMT1 expression and activity. Results:: Our results have identified twenty (20) medicinal compounds that reduced the expression of DNMT1 up to 50-77% as compared to the standard cytosine analog (91.5%). These compounds have also interacted with the reported active site residues of DNMT1, as predicted by IGEMDOCK. These compounds have adequate druglikeness, toxicity, and pharmacokinetic properties as described by Protox-II and ADMET lab 2.0. Conclusion:: Thus, our study provides an initial report of those medicinal compounds that have DNMT1 targeting ability and have a relatively safer pharmacokinetic and toxicity profile.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139756055","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":"In silico Structure-based Screening of Potential Anticancer Bioactive Natural Constituents from African Natural Products","authors":"Khairedine Kraim, Atidel Boudjedir, Youcef Saihi, Fatima Zohra Oueld Chikh, Yassira Slatnia, Fouad Ferkous","doi":"10.2174/0115701808280302240117055932","DOIUrl":"https://doi.org/10.2174/0115701808280302240117055932","url":null,"abstract":"Introduction: Inhibitors of topoisomerases, essential regulators of cancer development, are promising as cancer treatments. These enzymes regulate DNA topology and eliminate topological constraints during various biological processes, including replication, transcription, and recombination. Nature has continually offered scientists pathways to explore the development of new drugs. Indeed, since ancient times, various plant extracts have been utilized in treating multiple pathologies. Objective: It’s intriguing to diversify the therapeutic classes of natural topoisomerase 1 inhibitors. We aimed to explore the relationship between the toxicity of certain medicinal plants in North Africa and their anti-topoisomerase 1 enzyme activity. This investigation aims to discover potentially valuable compounds for fighting cancer by inhibiting the Topo1 enzyme, enriching the anticancer therapeutic class. Methods: This study has conducted a virtual screening of the African Natural Products Database to identify new scaffolds as topoisomerase 1 inhibitors. Molecular docking as a structure-based drug design approach was selected as one of the best approaches, and the complex code ID: 1K4T was used for this purpose. Results and Discussion: The molecular docking of more than 5790 natural products extracted from this database was docked into the binding site of the above-cited complex using the Modlock optimizer and Moldock score as search and scoring function algorithms, respectively. The top-ranked compounds have been assessed, analyzed, and compared to Topotecan and Irinotecan as reference ligands and drugs. Conclusion: Consequently, the seven natural products have shown a strong affinity to topoisomerase 1 and DNA. They establish a clear link between topoisomerase 1 inhibition and the anticancer activity of their corresponding plant extracts. Therefore, these hits are promising and serve as a base for further development of new topoisomerase 1 inhibitors.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139756175","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":"Computational Insights on Migraine and Anxiety in Association with BDNF","authors":"Sakthi Sasikala Sundaravel, Beena Briget Kuriakose, Sakeena Mushfiq, Karthikeyan Muthusamy","doi":"10.2174/0115701808274096231207042744","DOIUrl":"https://doi.org/10.2174/0115701808274096231207042744","url":null,"abstract":"Background:: Migraine is an unusual piercing headache on one side of the head. It is due to the dysregulation of epigenetic factors associated with the brain. Migraine affects about one percent of the general population. Despite the recent implementation of worldwide diagnostic criteria for migraine, this disorder remains relatively unknown and is frequently underdiagnosed. Migrainous conditions are also associated with anxiety and stress. This pathologic condition affects the daily life and productivity of the patients. Objective:: Hence, there is a need to develop proper treatment and management strategies to cope with migraine and associated anxiety. Through in silico approaches, this work elucidates to identify the effective lead compounds for migraine and anxiety. Methods:: Brain-derived neurotrophic factor (BDNF) was identified as a possible target for treating migraine and anxiety using computational analysis. Virtual screening and molecular dynamics simulation were used to find potential agonists with high affinities for BDNF. Results:: Based on the results of computational analysis (glide XP score, number of interactions, glide energy, and pharmacokinetic factors), four top hit molecules (Asinex_35922, Enamine_44630, Maybridge_1999, and SMMDB_17457) were identified and taken for further analysis. The hydrogen bond interactions between the agonists and the BDNF protein were verified by dynamics analysis Conclusion:: Computational studies support that BDNF agonist molecules could be effective regulating molecules for migraine and anxiety. For further evidence of the effectiveness of lead compounds in treating migraine and related anxiety, more experimental studies are necessary.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139756178","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":"Essential Structural Profile of Novel Adenosine Derivatives as Antiplatelet Aggregation Inhibitors based on 3D-QSAR Analysis","authors":"Shunlai Li, Pengyu Zheng, Yajing Ren, Hongguang Du","doi":"10.2174/0115701808247583231124062525","DOIUrl":"https://doi.org/10.2174/0115701808247583231124062525","url":null,"abstract":"Aims: In this research, 3D-QSAR evaluation on a set of fresh purinoid compounds that we produced was conducted. This analysis aims to illustrate the correlation between the structure of purine and its ability to prevent platelet aggregation. Our findings could pave the way to discovering novel antithrombotic medications. background: Cardiovascular disease caused by platelet aggregation is a serious threat to human health. Purine derivatives are important molecules with antiplatelet aggregation activity. Background: The incidence of cardiovascular disease triggered by the clumping of platelets poses a significant danger to human health. Purine derivatives are important molecules with antiplatelet aggregation activity. Objective: The objectives of this research are to establish the correlation between the structure of purine and its ability to prevent platelet aggregation. Such a correlation could aid in the development of innovative antithrombotic medications. method: In this study, 3D-QSAR analysis was performed on a series of novel purine derivatives synthesized by us based on comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). Methods: In this study, 3D-QSAR investigation on a collection of 75 new purine derivatives, which we synthesized, was conducted, utilizing Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). result: Significant correlation coefficients (CoMFA, q2=0.843, r2=0.930, F value=266.755, SEE=0.165; CoMSIA, q2=0.869, r2=0.918, F value=222.571, SEE=0.179) were obtained, and the model prediction ability was validated using the test set. Results: Significant correlation coefficients (CoMFA, q2= 0.843, r2= 0.930, F value= 266.755, SEE= 0.165; CoMSIA, q2= 0.869, r2= 0.918, F value= 222.571, SEE= 0.179) were obtained, and assessed the model's predictive capabilities by validating it with the test set. conclusion: The results suggest that it is beneficial to introduce a group of appropriate size at position C-2 of the purine ring, and that an excessively large group is disadvantageous; a bulky substituent group cannot be directly attached at the C-6 position of the purine ring, and the attachment of a group with low electron cloud density increases the activity, and the attachment of a bulky group at the C-5' of the sugar ring is beneficial, and the presence of hydrogen bond receptors in this region also increases the activity. Conclusion: Our findings indicate that the introduction of an appropriately sized structure at position 2 of the compound yields significant benefits. Conversely, the attachment of an excessively large group is detrimental. Direct attachment of a bulky substituent at C-6 of the compound is not feasible, and its activity increases when the structure with low electron cloud density is added. Moreover, the presence of a voluminous functional group at the 5' position of the compound is advantageous, and its ","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139670315","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":"Computational and In vitro Elucidation of Indolenine-barbituric Acid Zwitterions as Potential Chemotherapeutical Agents","authors":"Kang Kit Ong, Abdul Qaiyum Ramle, Min Phin Ng, Siew Huah Lim, Kae Shin Sim, Chun Hoe Tan","doi":"10.2174/0115701808279494231206060106","DOIUrl":"https://doi.org/10.2174/0115701808279494231206060106","url":null,"abstract":"Introduction:: The continuous pursuit of novel chemotherapeutical agents with improved efficacy and reduced adverse effects remains a critical area of research despite advancements in chemotherapy. We have previously synthesized indolenine and barbituric acid zwitterion scaffolds 1–10 sustainably; however, their precise chemotherapeutical properties are still lacking. Methods:: In this present work, we conducted in silico ADMET analyses, molecular docking calculations, DNA binding studies, and cytotoxicity assays on these zwitterions. Results and Discussion: Among the 10 zwitterions, zwitterion 3 bearing a methoxy group demonstrated the highest drug-likeness score, low toxicity, as well as no violation of Lipinski’s rule of five and Veber’s rule. Both molecular docking calculations and DNA binding studies suggested that the minor groove of DNA is the most probable molecular target of 3 among the others (i.e., topoisomerase and tubulin). In addition, zwitterion 3 exhibited selective cytotoxicity against a wide array of human cancer cell lines without noticeable effect against the normal human colon fibroblast CCD- 18Co. Conclusion:: Overall, these preliminary findings from our combined computational and experimental strategy suggested that 3 remains promising for further elaboration as a chemotherapeutic agent.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139663201","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":"A Comprehensive Review of the Advancement in Omic Technologies in the Field of Drug Discovery and Development","authors":"Mridula Chauhan, Shivansh Kumar, Arpon Biswas, Mukesh Kumar, Sarvesh Kumar Verma, Anjali Mishra, Vaishali Singh, Amol Chhatrapati Bisen, Sristi Agrawal, Abhijit Deb Choudhury, Ramkrishna Rayiti, Rabi Sankar Bhatta","doi":"10.2174/0115701808287654240126112003","DOIUrl":"https://doi.org/10.2174/0115701808287654240126112003","url":null,"abstract":": Discovering new drugs is time-consuming and expensive and involves many different tools from various domains. Numerous omic technologies, such as genomics, transcriptomics, proteomics, and metabolomics, have been created to speed up the process. Leveraging genetic and genomic insights, these methodologies play a pivotal role. Genetic insights aid in target identification, prioritization, and the prediction of drug outcomes. Gene expression data informs drug discovery, while proteomics uncovers targets and facilitates high-throughput profiling. Enhancing drug efficacy necessitates mechanistic insights into downstream effects, enabling side effects and resistance prediction. Early-stage drug discovery now extensively employs diverse metabolomics platforms. This review underscores the recent strides of omic technologies in drug discovery, affirming their role in enhancing drug viability and regulatory approval. The emphasis lies on the latest advancements in genomics, transcriptomics, proteomics, and metabolomics, collectively fortifying drug development.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139665512","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":"Therapeutic Voyage of Graphene-based Biosensor","authors":"Rama Sharma","doi":"10.2174/0115701808291102240130113741","DOIUrl":"https://doi.org/10.2174/0115701808291102240130113741","url":null,"abstract":": The study of carbon-based materials and nanoparticles is currently an exciting field of study in the domain of material science. One of the most prominent of these materials is graphene, along with its related components graphene oxide and reduced graphene oxide. A single-layer, twodimensional nanomaterial called graphene (GN) is employed in many different industries, such as electronics and biology. Graphene is a remarkable two-dimensional substance that has earned the title of \"wonder material.\" Its remarkable electrical, optical, thermal, and mechanical qualities have attracted significant attention. Graphene's intriguing characteristics have led to its integration into numerous biosensing applications. Graphene possesses remarkable chemical, electrical, and physical qualities. The distinctive properties of graphene, particularly its electrical conductivity, large surface area, and significant electron mobility, are focusing more attention on applications in biomedicine that facilitate easier health monitoring. Biosensors with high sensitivity and precision can enhance patient care, and offer an opportunity for an early illness diagnosis and clinical pathogen identification. Additionally, a wide range of biological molecules, including glucose, hydrogen peroxide, cholesterol, dopamine, etc., can be detected using graphene-based biosensors. This study evaluates contemporary developments regarding graphene-based biosensors and their prospects and difficulties in this rapidly developing profession in the coming era. Graphene-based nanomaterials are appropriate to be employed in various biological and sensory contexts, including medicine and gene transfer, because of their unusual topologies and extraordinary properties. Graphene's outstanding characteristics enable biosensing applications to obtain the appropriate sensitivity, selectivity, and repeatability for a range of targets.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139663132","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":"QSAR Analysis and Molecular Docking Studies of Aryl Sulfonamide Derivatives as Mcl-1 Inhibitors and the Influence of Structure and Chirality on the Inhibitory Activity","authors":"Jia Chen, Yang Ma, Jian-Wei Zou, Sheng Hu, Meilan Huang, Guixiang Hu","doi":"10.2174/0115701808278918240109053316","DOIUrl":"https://doi.org/10.2174/0115701808278918240109053316","url":null,"abstract":"Background:: Mcl-1 is a kind of antiapoptotic protein and its overexpression is closely related to the occurrence of cancer. Aryl sulfonamide derivatives are expected to become new anticancer agents due to their high inhibitory activity on the Mcl-1 protein. Objective:: The study aimed to establish the QSAR model with good prediction ability and elaborate the influence of structure and chirality on the inhibitory activity. method: Multiple QSAR models were built with different types of descriptors and modeling methods. The molecular docking was performed on compound 45, 25, 26, 24R and 24S. Results:: The comprehensive models including 2D and 3D descriptors demonstrated that nonlinear LSSVM and GP methods gave better results (R2>0.94, RCV2>0.86). The training set had a good predictive power on the test set. The predictive performances of MCCV tests are basically coincident with the results of the single test set. The results of molecular docking showed that the hydrogen bond acceptor at the appropriate position of the substituent on the chiral center can form the hydrogen bond interaction with residue ASN260, which results in the stronger interaction between ligand and protein and higher inhibitory activity. The interaction differences between R and S configuration with Mcl-1 protein are mainly attributed to two residues, HIS224 and ASN260. Two opposite effects lead to the activity of R enantiomer slightly higher than that of S one. The results on chiral compound 24 with ambiguous absolute configuration demonstrated that the steric effect of the substituents on chiral carbon atom is crucial. When there are two substituents with big volume at the same time, high steric effect will prevent the binding of the substituent and the protein, which results in the low inhibitory activity. Conclusion:: The study may provide theoretical guidance on the design and synthesis of novel aryl sulfonamide derivatives with high inhibitory activity","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139663544","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}