Letters in Drug Design & Discovery最新文献

{"title":"Pyrazolone Derivatives: Synthetic Chemistry, Exploring Pharmacological\u0000Activity - A Mini Review","authors":"Shilpi Pathak, Sonia Singh, N. Agrawal","doi":"10.2174/0115701808305582240604113524","DOIUrl":"https://doi.org/10.2174/0115701808305582240604113524","url":null,"abstract":"\u0000\u0000Pyrazolone has a wide range of biological activities, including anti-inflammatory, antibacterial,\u0000antifungal, antimicrobial, anti-tubercular, anti-oxidant, anti-helminthic, and anticancer\u0000effects. Due to their various clinical practice and research activities, they have a wide range of applications\u0000and prospects. They continue to be the subject of many research and analytical studies to\u0000learn more about their medicinal chemistry. In this review, pyrazolone is categorized according to its\u0000effects, which might include anti-inflammatory, antifungal, antibacterial, antimicrobial, antitubercular,\u0000anti-oxidant, anti-helminthic, anticancer, or antitumor, as well as other qualities. As a\u0000result, it is crucial to base the design of new pyrazolone derivatives and the development of innovative\u0000synthesis techniques on the most recent data gleaned from recent studies. The goal of this review\u0000is to provide information on developments in the chemistry and biological activity of pyrazolone\u0000derivatives.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141348972","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":"Enhanced Permeation Retention Effect - Modeling and Imaging Approaches for Nanoparticle-Mediated Anti-cancer Diagnostics or Therapy","authors":"Suresh P.K.","doi":"10.2174/0115701808306902240604071741","DOIUrl":"https://doi.org/10.2174/0115701808306902240604071741","url":null,"abstract":"\u0000\u0000This perspective focuses on the hyper-permeable vasculature, contributing to the passive\u0000accumulation of drugs or NP-drug combinations through the paracellular and/or transcellular pathways.\u0000This unique, cardinal, pathological feature of the vasculature in solid tumors is a major determinant\u0000for the entry of anti-cancer macromolecules, with longer drug retention, attributable to imperfections\u0000in the lymphatic drainage system. However, the desmoplastic reaction, another challenge in\u0000terms of drug delivery, is attributable to the collagen-dense, heterogeneous accumulation of stromal\u0000components in the Tumour Microenvironment (TME). Thus, the consequent increases in the Interstitial\u0000Fluid Pressure (IFP) have been determined by experimental and computational techniques. This\u0000back-flow can contribute to decrements in the drug/NP-drug conjugate reaching the tumour site,\u0000warranting strategies to be adopted that can lower this pressure. However, the translational potential\u0000of the EPR-effect-mediated drug delivery in humans is limited. The tumour-specific, spatiotemporal\u0000differences in the EPR effect require human-relevant tumour models as well as their analysis based\u0000on advanced imaging, including MRI-based studies. This development, validation, and refinement of\u0000an iterative strategy can lead to the optimization of such customized models for personalised, tailormade\u0000medicine.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141354276","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":"Rheum khorasanicum Decreases Migration and Induces Apoptosis in the MDA-MB-231 Breast Cancer Cell Line","authors":"M. Mehrabani, Zahra Miri, Kobra Bahrampour Juybari, R. Najafi, Maryamossadat Mirtajaddini Goki, N. Aminizadeh, M. Nematollahi, Saeede Vasei, M. Mehrabani, Arian Amirkhosravi","doi":"10.2174/0115701808297489240531111626","DOIUrl":"https://doi.org/10.2174/0115701808297489240531111626","url":null,"abstract":"\u0000\u0000N/A\u0000\u0000\u0000\u0000Rheum khorasanicum belongs to the Polygonaceae family, which is well-known for its anticancer activities.\u0000\u0000\u0000\u0000Due to the limited studies on the anticancer activity of R. khorasanicum, the present study aimed to evaluate the apoptotic effect of this medicinal plant on MDA-MB-231 cells as a model for an aggressive triple negative breast cancer that has lower treatment option.\u0000\u0000\u0000\u0000The high-performance thin layer chromatography (HPTLC) assay was used for determining the main ingredients of the extract. Viability and apoptosis of the cells was evaluated by WST-1 and the annexin-V/PI dual staining assay, respectively. The scratch assay was used to assess the cellular migratory potential, and the western blotting test was employed for determining the expression of proteins involved in the apoptotic pathway.\u0000\u0000\u0000\u0000The HPTLC analysis indicated that emodin, gallic acid, epicatechin gallate, and rhaponticin are pharmacologically active compounds isolated from the hydro-alcoholic extract of R. khorasanicum. The extract showed a significant toxic effect on MDA-MB-231 cells. R. khorasanicum extracts also inhibited cellular migratory potential at concentrations higher than 60 μg/mL. The plant extract significantly diminished the Bcl-2/Bax ratio and increased cleaved caspase- 3, cleaved caspase-7/ procaspase-7 expression at protein levels compared to the nontreated cells.\u0000\u0000\u0000\u0000Our findings demonstrated that effect root extract efficiently triggered the death of breast cancer cell lines possibly through the stimulation of the apoptotic signaling pathway.\u0000\u0000\u0000\u0000N/A\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141361865","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":"Isoquercetin Neuroprotective Molecular Targets in Parkinson’s Disease: Recent Highlights and Future Perspectives","authors":"Dilpreet Kaur, Shamsher Singh","doi":"10.2174/0115701808294683240531111346","DOIUrl":"https://doi.org/10.2174/0115701808294683240531111346","url":null,"abstract":"\u0000\u0000Parkinson's disease (PD) is an age-related progressive neurodegenerative condition characterized\u0000by dopaminergic neuronal loss in the brain's substantia nigra pars compacta (SNpc). Growing\u0000evidence suggests that apoptosis, neuroinflammation, mitochondrial dysfunction, and oxidative\u0000stress are important factors in the pathogenesis of Parkinson's disease. Isoquercetin is a natural flavanol\u0000compound possessing anti-apoptotic, anti-inflammatory, anti-oxidant, and neuroprotective\u0000activities. Isoquercetin also has the capability to modulate various signaling pathways such as Rho\u0000signaling cascade, Nrf-2, TLR4, NF-κB, MAPK, Bcl-2, Bax proteins, which are well-known causes\u0000for the progression of the disease. These pathways are involved in cellular homeostasis, transcription\u0000of proinflammatory cytokines, oxidative stress, microglial activation, and regulation of the apoptotic\u0000pathways. In this review, we have highlighted the mechanisms of the above-mentioned pathways and\u0000their modulation via the flavonoid compound isoquercetin in various ways.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141365164","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":"Unveiling Novel HIV-1 Protease Inhibitors through an Integrated Analysis of 3D-QSAR, Molecular Docking, and Binding Free Energy","authors":"Guozheng Zhou, Yujie Shi, Yan Li","doi":"10.2174/0115701808300511240527130649","DOIUrl":"https://doi.org/10.2174/0115701808300511240527130649","url":null,"abstract":"\u0000\u0000HIV-1, the primary causative agent of AIDS, remains a formidable and\u0000lethal virus globally, claiming the lives of millions over the past four decades since its discovery.\u0000Recent research has underscored the potential of HIV-1 protease as a therapeutic target, offering a\u0000promising strategy for inhibiting viral replication within the body.\u0000\u0000\u0000\u0000In light of this, we have curated an extensive database comprising 193 derivatives of Darunavir\u0000(DRV), an HIV-1 protease inhibitor. Simultaneously, we have developed a comprehensive\u0000set of 3D-QSAR models to elucidate the structure-activity relationships of these 193 derivative inhibitors.\u0000Employing various computational simulation techniques, including Comparative Molecular\u0000Field Analysis (CoMFA), Comparative Similarity Indices Analysis (CoMSIA), and molecular docking,\u0000we have unveiled the fundamental three-dimensional structural features influencing their biological\u0000activity.\u0000\u0000\u0000\u0000Results indicate that the optimal CoMSIA model (Q2 = 0.500, R2\u0000ncv = 0.882, R2\u0000pred = 0.797)\u0000surpasses other models, demonstrating superior predictive capability. Furthermore, docking results\u0000suggest that DRV derivatives maintain stable conformations within the binding cavity due to synergistic\u0000interactions, such as hydrogen bonding and non-bonded interactions. Drawing insights from\u0000the best computational models, we have designed five DRV derivatives with significant HIV-1 protease\u0000inhibitory activity through local modification, with theoretical calculations indicating favorable\u0000pharmacokinetic properties and synthetic feasibility for the newly proposed molecules.\u0000\u0000\u0000\u0000It is hoped that the findings and conclusions obtained herein may furnish theoretical\u0000underpinning and directional guidance for the design, optimization, and experimental synthesis of\u0000DRV derivative compounds for pharmaceutical purposes.\u0000\u0000\u0000\u0000In conclusion, this research identifies key residues, including Asp25, Gly27, Asp29, Asp30, Asp124, and Asp129, as significant for ligand binding. The information derived from the in silico models contributes to the design of five newly proposed DRV derivative compounds as promising HIV-1 protease inhibitors, surpassing the inhibitory activity of compound 171. The study holds potential for optimizing Darunavir derivatives in the development of anti-HIV-1 protease drugs.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141388331","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":"Construction of an Adenovirus Vector with Laco-regulated Antigen Expression Using the SARS-Cov-2 Spike as a Transgene Model","authors":"A. Artarini, Annisa Rahma Bassalamah, Arrie Arifa Arbuati, Tia Hadianti, Katherine Vanya Prasetya, Marselina Irasonia Tan, Dessy Natalia, C. Riani, E. Giri-Rachman","doi":"10.2174/0115701808293712240516105131","DOIUrl":"https://doi.org/10.2174/0115701808293712240516105131","url":null,"abstract":"\u0000\u0000The adenovirus vector has been widely studied for vaccines and gene therapies.\u0000During the production of the adenovirus vector, a high virus titer is desired to obtain enough\u0000virus. The adenovirus vector has been widely studied for the vaccinations and gene therapies, where\u0000a high virus titer is desired to obtain sufficient quantities of the virus. For an adenovirus vector-based\u0000vaccine, suppression of antigen expression during production would improve the virus titer during\u0000production.\u0000\u0000\u0000\u0000This study aimed to construct an adenovirus vector with lacO-regulated antigen expression\u0000using the SARS-CoV-2 spike as a transgene model, which would improve the adenovirus titer\u0000during production. Methods: The lacO expression cassette was designed and prepared as a synthetic\u0000gene in pUC57. The lacO expression cassette was then subcloned into pShuttle-CMV. The SARSCoV-\u00002 spike gene was then inserted into the pShuttle-CMV harboring lacO to generate pShuttlelacO_\u0000S and pShuttle-lacO-intron_S. Recombinant pShuttle was then used to generate a recombinant\u0000adenovirus genome using Escherichia coli BJ5183 pAdeasy-1. Transfection of the PacI-linearized\u0000adenovirus genome into AD293 and HEK293 cells was used to generate adenovirus primary stock\u0000for 14 days of incubation.\u0000\u0000\u0000\u0000Recombinant adenovirus genomes, pAdeasy-lacO_S and pAdeasy-lacO-intron_S, were\u0000successfully generated and characterized using PacI restriction and PCR. In the production of adenovirus\u0000primary stocks, the adenovirus titer produced in AD293 cells was higher than in HEK293\u0000cells. The primary stock titer of AdV_lacO-intron-S was higher than AdV_lacO-S and AdV_S titers.\u0000\u0000\u0000\u0000Production of adenovirus with lacO and spike gene, either with or without intron, was\u0000successful with a higher titer as compared to AdV_S titer.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141116994","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 Biological Evaluation of Cephalosporin Based Metallo-β-lactamase\u0000(MBL) Inhibitors#","authors":"Shaan Patel, Pradip A Jadav, R. Bahekar, Kumargurubaran Nagaswamy, Kasinath Viswanathan, Purvi Vyas, Poonam Giri, Sachchidanand S, Mukul Jain","doi":"10.2174/0115701808287192240415062148","DOIUrl":"https://doi.org/10.2174/0115701808287192240415062148","url":null,"abstract":"\u0000\u0000Prevalence of microbial resistance due to Metallo-β-lactamase (MBL) enzyme pose a serious threat to human life. MBLs depend on active site zinc for their hydrolytic activity; hence, the investigation of zinc chelators emerged as an attractive strategy for the development of\u0000potent MBL inhibitors.\u0000\u0000\u0000\u0000To prove that such chelators selectively target MBLs, in the present investigation, novel\u0000cephalosporins based MBL inhibitors (Cef-MBLi) were designed as a conjugate of cephalosporins\u0000with a potent zinc binder 8-thioquinoline (8-TQ).\u0000\u0000\u0000\u0000Cef-MBLi showed site specific release of conjugate only in the presence of a Veronaintegron encoded metallo-β-lactamase 2 (VIM-2) bacterial enzyme through hydrolytic cleavage\u0000mechanism. A total of 6 (4a-e and 6f) New Chemical Entities (NCE’s) were prepared, characterized\u0000and subjected for in vitro study.\u0000\u0000\u0000\u0000Among tested NCE’s, 4c showed potent MBL inhibitory activity against the VIM-2\u0000enzyme.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140660586","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":"Conducting 2D and 3D QSAR Analyses and Molecular Docking Studies of Analogues of 2-(1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl)ethan-1-ol with the\u0000Aim of Identifying Promising Drug Candidates for Targeting Glioblastoma","authors":"Meichen Pan, Lingxue Cheng, Yi-guo Wang, C. Lyu, Chao Hou, Qiming Zhang","doi":"10.2174/1570180820666230901162718","DOIUrl":"https://doi.org/10.2174/1570180820666230901162718","url":null,"abstract":"\u0000\u00002-(1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl) ethan-1-ol analogues represent novel\u0000glutaminase 1 inhibitors. Their exemplary antineoplastic efficacy underscores their prospective utility in\u0000glioblastoma chemotherapy.\u0000\u0000\u0000\u0000This study aimed to elucidate 2D and 3D-QSAR models that authenticate the antineoplastic\u0000efficacy of ethan-1-ol analogues and delineate optimal structural configurations conducive to new pharmaceutical\u0000design.\u0000\u0000\u0000\u0000The Heuristic Method (HM) was employed for the development of a 2D-linear QSAR paradigm,\u0000whilst the Gene Expression Programming (GEP) algorithm was employed for a 2D-nonlinear\u0000QSAR paradigm. Concurrently, the CoMSIA methodology was deployed to scrutinize the nexus between\u0000pharmaceutical structure and potency. An ensemble of 200 nascent anti-glioma ethan-1-ol compounds\u0000was conceptualized, and their potency levels were prognosticated via chemical descriptors and molecular\u0000field delineations. Pharmaceuticals epitomizing peak potency were earmarked for molecular docking\u0000validation.\u0000\u0000\u0000\u0000The empirical modeling exhibited pronounced superiority with the 3D paradigm, succeeded by\u0000the GEP nonlinear paradigm and culminated with the HM linear model. The 3D paradigm was characterized\u0000by a robust Q2 (0.533), R2 (0.921), and F-values (132.338) complemented by a minimal SEE\u0000(0.110). The molecular descriptor MNO coupled with the hydrogen bond donor field facilitated novel\u0000pharmaceutical conceptualizations, leading to the identification of the quintessential active molecule,\u000024J.138, lauded for its superlative antineoplastic attributes and docking proficiency.\u0000\u0000\u0000\u0000The orchestration of bidimensional and tridimensional paradigms, synergized by innovative\u0000amalgamation of contour maps and molecular descriptors, provides novel insights and methodologies for\u0000the synthesis of glioblastoma chemotherapeutic agents.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89899848","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, Computational Study of β-lactam Derivatives Bearing Quinazoline Schiff Bases as Anthelmintics","authors":"Gurdeep Singh, Ritesh Patel, Alok Singh Thakur, Mukesh Kumar Singh","doi":"10.2174/1570180820666230901121339","DOIUrl":"https://doi.org/10.2174/1570180820666230901121339","url":null,"abstract":"\u0000\u0000Infections caused by parasites continue to pose a risk to both human and animal\u0000health. The most popular drug classes for treating these infections include thiabendazole, imidazothiazoles,\u0000levamisole, and avermectins (obtained from the fermentation products of Streptomyces\u0000avermitilis). The majority of bacteria that we come across in any form of infection are successfully\u0000combatted by β- lactam medicines. Similar to the majority of treatments, problems with treatment\u0000resistance to these drugs have evolved over time, necessitating the development of new anthelmintic\u0000medications. This study aims to investigate a series of quinazoline-bearing β-lactam rings as potent anthelmintic\u0000agents.\u0000\u0000\u0000\u0000The new series of quinazoline bearing β-lactam was synthesized via reaction of 5-bromo\u0000anthranilic acid with acetic anhydride to produce 6-bromo-2-methyl-4H-benzo (1,3) oxazin-4-one which\u0000was then converted into 3-amino-6-bromo-2-methylquinazolin-4(3H)-one by the reaction of hydrazine\u0000hydrate in the presence of anhydrous pyridine. The resultant intermediate then goes through a Schiff\u0000reaction with various aromatic aldehydes, followed by reflux with triethylamine and chloroacetyl\u0000chloride.\u0000\u0000\u0000\u0000Structural assignments of these compounds have been made by elemental analysis,\u0000FTIR,1HNMR and Mass spectral data and the purity of the compounds was determined by TLC. Molecular\u0000docking studies showed the effective binding of synthesized derivatives with tubulin in comparison to\u0000the orientation of standard drugs. The anthelmintic activities of all the synthesized compounds were evaluated\u0000separately for their possible using common Indian earthworm Pheritima posthuma.\u0000\u0000\u0000\u0000A total of ten derivatives of quinazoline bearing β-lactam ring were designed, synthesized\u0000and evaluated against the Indian earthworm Pheritima posthuma. Out of ten derivatives, SQD2 and\u0000SQD6, showed promising anthelmintic activity when compared with standard drugs albendazole and\u0000piperazine citrate.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75980044","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":"In-silico Screening of Novel Diterpene Derivatives for their Inhibitory Potentials against MurA Enzyme of Uropathogenic Escherichia coli","authors":"Abhishek Chowdhury, M. A. Laskar, M. Choudhury","doi":"10.2174/1570180820666230831095945","DOIUrl":"https://doi.org/10.2174/1570180820666230831095945","url":null,"abstract":"\u0000\u0000Enzyme UDP-NAG enolpyruvyl transferase (MurA), which aids in the formation of cell walls and is identified as the primary target of the antibiotic Fosfomycin, is a significant pharmacological target in the case of uropathogenic Escherichia coli (UPEC). Finding a potent drug with a distinct mode of action is required since UPEC treatment is challenging due to resistance and resurrection.\u0000\u0000\u0000\u0000Here we have used virtual high-throughput screening and molecular dynamics simulation approach to explore the effectiveness of selected novel Diterpene derivatives against the therapeutic target MurA (both wild type and Cys115Asp mutant, which is responsible for lower effectiveness of Fosfomycin).\u0000\u0000\u0000\u0000The investigation showed improved binding efficacy of the ligands around the primary active site residue Cys115 as well as enhanced activity against Cys115Asp mutant. Against wildtype receptors, the docking score of best-docked diterpene derivative, DIT1 (-26.18) was found to be much better than that of the known drug, Fosfomycin (-23.72). There were 7 nos of hydrogen bonds formed by DIT1 and 5 nos by Fosfomycin, indicating a stronger interaction of DIT1 with MurA. The mutant form also showed similar findings, suggesting that DIT1 is much more effective than Fosfomycin.\u0000\u0000\u0000\u0000The above result justifies the potential of Diterpene derivatives in blocking the MurA active site that can prevent peptidoglycan biosynthesis. Effectiveness of DIT1 against wild type as well as Cys115Asp mutant justifies that the selected ligands can be used as suitable drug candidates against MurA to add new molecules in the treatment pipeline. This establishes innovative frameworks for the creation of strong drugs that target MurA after suitable in-vitro and in-vivo trials.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83060587","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}