Letters in Drug Design & Discovery最新文献

{"title":"A Review on Synthesis and Biological Potential of Dihydropyridines","authors":"Shilpi Pathak, Supriya Jain, Abhishek Pratap","doi":"10.2174/1570180820666230508100955","DOIUrl":"https://doi.org/10.2174/1570180820666230508100955","url":null,"abstract":"\u0000\u0000Dihydropyridine is an outstanding heterocyclic compound with a wide range of pharmacological potential, including antimicrobial, antioxidant, antitubercular, antiarrhythmic, insecticidal, antihypertensive, vasodilator, anti-inflammatory, antibacterial, antidiabetic and superlative moiety in drug discovery. It is also a versatile pharmacophore, a privileged scaffold, and a distinguished heterocyclic compound. Excellent outcomes have already been shown with novel targets and various modes of action for the dihydropyridines hybrids. This review focused on the mode of action, synthesis, and biological activities. As a result, numerous dihydropyridine candidates are undergoing clinical studies to treat various disorders. This article highlights how novel techniques were used to create dihydropyridines, which may be helpful to researchers in the future.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86904727","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":"Palladium (II)-N-heterocyclic Carbene Complexes: Synthesis, molecular Docking, UV-Vis Absorption and enzyme inhibition","authors":"Sofiane ikhlef, Sarra Lasmari, E. H. Mokrani, R. Boulcina, C. Bensouici, N. Gürbüz, I. Özdemir","doi":"10.2174/1570180820666230508154948","DOIUrl":"https://doi.org/10.2174/1570180820666230508154948","url":null,"abstract":"\u0000\u0000Alzheimer's disease is the most prevalent form of dementia; it affects the brain regions responsible for thought, memory, and language. Dementia cannot currently be cured by any medication.\u0000\u0000\u0000\u0000We aimed to synthesize Pd-NHC type PEPPSI and investigate their biological activity in anticholinesterase enzymes.\u0000\u0000\u0000\u0000In this study, we described preparing a series of Pd-NHC type PEPPSI obtained from their unsymmetrical benzimidazolium salts. These complexes (3a-f) were synthesized from the 2-chloromethyl-1,3-dioxalane benzimidazolium salts, PdCl2, KBr and pyridine. The compounds (3a-f) were tested against two enzymes (AChE and BChE).\u0000\u0000\u0000\u0000The results showed that most of the Palladium–NHC complexes effectively inhibited AChE with IC50 values in the range of 4.94 - 40.03 μM, and for BChE are in the range of 4.21 - 21.28 μM. The results showed that the compound (3a) was the most potent inhibitor activity against both AChE and BChE. The inhibition parameter (IC50) was calculated by the spectrophotometric method. The inhibitory effects of the synthesized Pd-NHCs were compared to galantamine as a clinical cholinergic enzyme inhibitor. Additionally, Molecular docking is carried out to estimate the binding pattern between the newly synthesized compounds and both AChE and BChE active sites.\u0000\u0000\u0000\u0000The results demonstrated that all synthesized compounds show excellent to moderate inhibition against the examined enzymes (AChE/BChE).\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90383890","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":"The implication of fragment-centric mapping strategy to explore the first selective inhibitor against target protein","authors":"Xie-Huang Sheng, Jia-Hui Zhao, Shaolong Zhang, Xia Zhou, Xian-Mei Meng, Ting-an Wang","doi":"10.2174/1570180820666230505124327","DOIUrl":"https://doi.org/10.2174/1570180820666230505124327","url":null,"abstract":"\u0000\u0000Identification of the first selective inhibitor, also called “hit molecules, \" is crucial for developing drugs against a protein target. However, the crystal structures of protein-ligand complexes are usually not resolved in time due to the process's time-consuming and costly nature. However, it does not prevent scientists from understanding the binding modes’ urgent advantages and drawbacks of protein-ligand interaction to guide the optimization of hit molecules.\u0000\u0000\u0000\u0000Here, we have developed a pocket-centric computational strategy to facilitate a comprehensive understanding of the hit molecules against the protein target.\u0000\u0000\u0000\u0000The results show that the pocket-centered mapping method not only allows for accurate prediction of the native docking pose and in-depth analysis of the binding mode but also has the potential of rapidly identifying partially unoccupied, unutilized, but targetable pockets to afford optimized hit molecules. We tested the strategy on the first selective inhibitor, epigallocatechin gallate (EGCG), against human arylacetamide deacetylase (AADAC). Molecular dynamics simulation and MM/PBSA binding energy calculation are used to verify the efficacy of the strategy.\u0000\u0000\u0000\u0000The results show that the pocket-centered mapping method not only allows for accurate prediction of the native docking pose and in-depth analysis of the binding mode but also has the potential of rapidly identifying partially unoccupied, unutilized, but targetable pockets to afford optimized hit molecules.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82855103","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, antimicrobial testing, and molecular docking studies of new chalcone and pyrimidine derivatives based on 2-phenyl-1H-pyrazol-3(2H)-one","authors":"R. Bakr, Ruba A. Alolayan, Nadia A. A. Elkanzi, H. Hrichi, Cyrine El Baher Dhafer, F. Zahou","doi":"10.2174/1570180820666230505142821","DOIUrl":"https://doi.org/10.2174/1570180820666230505142821","url":null,"abstract":"Heterocyclic pyrimidine and pyrazole rings have attracted the interest of medicinal chemists because of their pharmacological potential including antimicrobial activity. Based on molecular hybridization, new chalcones 6a-g and pyrimidines 7a-g based on a pyrazole scaffold were designed. The synthesis of these compounds involved mild condensation reactions between compound 4 and various aromatic aldehydes in a mixture of ethanol/NaOH (95:5 v/v) to give the corresponding chalcones 6a-g. These chalcones were further reacted with urea in the presence of a base in ethanol to produce the pyrimidine derivatives 7a-g. These new candidates were screened for their in vitro antimicrobial activities and molecular docking studies were evaluated. The antibacterial and antifungal studies of all synthesized compounds against the strains tested showed that compounds 6c, d, and 7c, d exhibited the highest antibacterial and antifungal activities. In addition, the structure-activity relationship and docking studies are discussed. The synthesized compounds 6c, 6d, 7c, and 7d showed the highest antibacterial and antifungal activities against the tested strains.","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89196969","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, Synthesis and Cytotoxic sSudies of Novel 4-anilinoquinazoline Derivatives of Potential Agents for Non-small-cell Lung Cancer","authors":"D. Dwivedi, Ram Kishore Agrawal, Sanyog Jain, Kaushik Kuche","doi":"10.2174/1570180820666230505123802","DOIUrl":"https://doi.org/10.2174/1570180820666230505123802","url":null,"abstract":"\u0000\u0000The pre-existing EGFR (Epidermal Growth Factor Receptors) inhibitors (Gefitinib, Afatinib and osimertinib) show significant resistance after one year of EGFR therapy in NSCLC (Non-small cell lung cancer) patients. With the aim of overcoming the resistance problem associated with a current therapeutic regimen, there is an imperative need for the development of novel 4-anilinoquinazoline derivatives that are specifically designed for resistance cases of NSCLC patients.\u0000\u0000\u0000\u0000We designed and synthesized eighteen 4-anilinoquinazolines derivatives as a novel scaffold and evaluated their anti-cancer potential against different NSCLC cell lines.\u0000\u0000\u0000\u0000Molecular docking study of designed compounds were performed on Glide v5.8 (Schrodinger, LLC, New York, NY). Synthesis of 4-anilinoquinazoline derivatives was performed, based on the docking score and was characterized by various spectroscopic methods. Further, in-vitro anti-cancer activity was performed using MTT assay on different cancer cell lines.\u0000\u0000\u0000\u0000Molecular docking analysis [EGFRT790M mutant (4I22)] indicated that most of these analogs (6g, 6j, 6l, 6m and 6o) were found to be higher docking scores than gefitinib. Furthermore, spectral analysis revealed that the designed compounds were synthesized successfully. The compounds 6a, 6d, 6g, 6i, 6j and 6m were identified as the potent inhibitors against (A431, H1975, A549) cell lines as compared to reference standard gefitinib. Excitingly, compound 6j (with IC50 values of 4.88±0.13, 4.38±0.08 & 11.97±0.14 µM) was identified as the most potent inhibitor for (A431, H1975, A549) cell lines.\u0000\u0000\u0000\u0000The study suggested that the six derivatives showed significant therapeutic potential against different NSCLC cell lines as compared to reference standard gefitinib.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73493157","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":"Analysis of ultrasound supported antımıcrobıal and antıbıofılm actıvıtıes of dısınfectıon by-product bromochloroacetonıtrıle","authors":"Sevda Er","doi":"10.2174/1570180820666230505085031","DOIUrl":"https://doi.org/10.2174/1570180820666230505085031","url":null,"abstract":"\u0000\u0000Some microorganism threaten human health by forming biofilm in water systems. Because microorganism in the biofilm structure are more resistant to antimicrobials.\u0000\u0000\u0000\u0000Water systems are disinfected with physical methods, such as ultrasonication techniques and chemical disinfectants. Bromochloroacetonitrile is produced as a by-product from algae and fulvic acid sources during water chlorination. This study aimed to investigate the antimicrobial and antibiofilm effects of bromochloroacetonitrile on some bacteria alone and with ultrasound treatment.\u0000The study used Escherichia coli ATCC 25922, Klebsiella pneumoniae MCTC 13438, and Staphylococcus aureus ATCC 25923 strains. The antimicrobial and antibiofilm activities of the test substance were analyzed alone with bromochloroacetonitrile and Ultrasound-assisted. Minimum Inhibitory Concentration values of the test substance against Escherichia coli ATCC 25922, Klebsiella pneumoniae MCTC 13438, and Staphylococcus aureus ATCC 25923 strains were 25, 25 and 50 mM, respectively, and Minimum Bactericidal Concentration values were 50, >50, and >50 mM, respectively.\u0000\u0000\u0000\u0000The obtained data show that bromochloroacetonitrile is a potential disinfection agent that can be used against biofilm formation in water systems. Besides, it was revealed that when ultrasound treatment was applied with bromochloroacetonitrile, it showed 100% antibiofilm activity on E. coli and K. pneumoniae and 79.45% antibiofilm activity on S. aureus strains. The obtained data show that bromochloroacetonitrile is a potential disinfection agent that can be used against biofilm formation in water systems. This study is preliminary and planned to reveal the cytotoxic effects of bromochloroacetonitrile on healthy human skin and liver cells in the following study.\u0000\u0000\u0000\u0000These results will contribute to the literature, as no study reveals the antimicrobial and antibiofilm activities of bromochloroacetonitrile.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82521460","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":"The Antiulcer and Hepatoprotective Effects of Euphorbia hirta Petroleum Ether, Chloroform and Ethanolic Extracts on Paracetamol-induced Ulcerated Wistar Rats","authors":"K. Srinivas, Senniappan Palanisamy, M. Rao","doi":"10.2174/1570180820666230505122331","DOIUrl":"https://doi.org/10.2174/1570180820666230505122331","url":null,"abstract":"\u0000\u0000Hepatic and gastric diseases are two of the most common ailments in people. Numerous researches have been conducted to evaluate the effectiveness of herbal remedies in the treatment of hepatitis and stomach ulcers.\u0000\u0000\u0000\u0000The study aimed to determine the antiulcer and hepatoprotective activities of Euphorbia hirta petroleum ether, chloroform and ethanolic extracts on paracetamol-induced ulcerated Wistar rats.\u0000\u0000\u0000\u0000Euphorbia hirta was collected from the area of Salem, Tamil Nadu, India. The air-dried whole plant was crushed, and 500 g of the powder and petroleum ether, chloroform and ethanol were used for continuous extraction by the Soxhlet device. Phytochemical analysis of the extract was done by conventional and GC-MS analysis. Nine sets of six male Wistar rats, each weighing between 150 and 200 g, were used in this study. The standard control group, Group I, received only 1% v/v tween 80. Group II, negative control, received saline (1ml/kg p.o.). Group III animals were given silymarin (200 mg/kg p.o.) and paracetamol (2g/kg), which served as the standard of care. Animals in groups IV, V, VI, VII, VIII, and IX received two separate doses (200 and 400 mg/kg) of petroleum ether, chloroform, and ethanolic extracts of Euphorbia hirta L. Liver tissue was taken for histological investigation and placed in a 10% formalin solution. The liquid supernatant of liver cells was used to measure antioxidant parameters, such as catalase, superoxide dismutase, and LPO.\u0000\u0000\u0000\u0000Phytochemical and GC-MS examination confirmed Euphorbia hirta extracts to have different biologically active phytoconstituents, like alkaloids, carbohydrates, glycosides, phenolic, flavonoids, tannin, sterols and alkaloids. Euphorbia hirta has been found to significantly protect against paracetamol-induced ulcer and hepatotoxicity compared to the negative control. A significant (p<0.001) reduction in SGPT, SGOT, ALP, DB and TB levels in the EEEH 400mg/kg extract-treated group was observed compared to the paracetamol group. The PEEH extract exhibited no significant decrease in all biochemical parameters compared to the negative control. However, the standard drug showed a significant (p<0.001) decrease when compared to the negative control. SGPT, ALP, and DB levels demonstrated a significant (p<0.01) reduction with EEEH 200mg/kg. The PEEH extract induced no significant decrease in all biochemical parameters compared to the negative control, and the chloroform extract of 200mg/kg showed a less significant (p< 0.05 & p<0.01) difference compared to the negative control. The histopathology study confirmed EEEH 200mg/kg to show good hepatoprotective activity.\u0000\u0000\u0000\u0000The findings have demonstrated Euphorbia hirta ethanolic extract to have effective antiulcer capabilities, and a decrease in LPO activity along with an increase in SOD, CAT, and LPO content have been observed, thereby leading to reduced oxidative stress. The antioxidant activity of Euphorbia hirta extract as a free radical scavenger and the hepa","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design &amp; Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78679259","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":"Oxidative biotransformation of organophosphotioate pesticides and acetylcholinesterase enzymatic inhibition","authors":"Daiana Teixeira Mancini, Isabela Aparecida Militani, Alexandre Alves de Castro, Teodorico de Castro Ramalho","doi":"10.2174/1570180820666230503095544","DOIUrl":"https://doi.org/10.2174/1570180820666230503095544","url":null,"abstract":"\u0000\u0000Pesticides have lethal properties, capable of controlling or eliminating a living\u0000organism; they block the organisms' vital metabolic processes. They cause serious problems for human\u0000health, as they are highly toxic. The most used pesticides that are considered toxic are known as organophosphothioates (OP/P=S) in their commercialized form and organophosphates (OP/P=O) in their active\u0000form. These compounds have been the subject of studies on their metabolism and toxicology. According\u0000to research, these pesticides' toxicity is increased when oxidative metabolic desulfurization reactions occur, with the P=S bond being transformed into a P=O bond. This toxicity is due to the ability of OP/P=O\u0000species to inhibit the human acetylcholinesterase enzyme (HssAChE).\u0000\u0000\u0000\u0000To study the oxidative biotransformation of OP/P=S pesticides and the inhibition of the HssAChE enzyme by OP/P=S and OP/P=O using the molecular docking technique and QM/MM calculations.\u0000\u0000\u0000\u0000The theoretical results showed that parathion is the compound with the greatest capacity to transform its P=S bonds into P=O bonds, thus forming the active paraoxon metabolite in the oxidative biotransformation process. In the HssAChE inhibition by OP/P=S and OP/P=O, our results showed that of all\u0000the compounds investigated, those with the highest inhibitory activities are parathion, paraoxon, malathion, diazoxon, chlorpyrifos and omethoate.\u0000\u0000\u0000\u0000This study was essential due to the lack of information in the literature about the oxidative\u0000biotransformation process of OP/P=S pesticides and the ability of these compounds to inhibit HssAChE.\u0000With this study, it was possible to observe that, in the oxidative biotransformation, chlorpyrifos and parathion have greater capacities to transform into their active metabolites and in the inhibition of the HssAChE enzyme, it was possible to observe that not all OF/P=O are the ones with the highest abilities to inhibit the HssAChE enzyme.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design &amp; Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74842267","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 Identification of Novel SphK1 Inhibitors","authors":"C. Kang, Jin Liu, H Zhao, Lei He, Ri-lei Yu","doi":"10.2174/1570180820666230503100040","DOIUrl":"https://doi.org/10.2174/1570180820666230503100040","url":null,"abstract":"\u0000\u0000In silico Identification of Novel SphK1 Inhibitors.\u0000\u0000\u0000\u0000A tumor is one of the major causes of death worldwide; the emergence of new targeted\u0000drugs has changed the mode of tumor treatment and opened up the era of targeted therapy. Sphingosine\u0000kinase 1 (SphK1) is a strictly conserved lipid checkpoint kinase, mainly located in the cytosol, and is\u0000overexpressed and enhances the development and progression of various type of tumors, such as melanoma, esophageal, gastric, and colon cancers. SphK1, consisting of 384 amino acid residues, has two\u0000domains: C-terminal (CTD) and N-terminal (NTD). SphK1 phosphorylates sphingosine to generate\u0000sphingosine-1-phosphate (S1P), which exists in high concentration in both the plasma and the lymph of\u0000cancer patients. S1P has 5 receptors (S1PRs) and controls 5 signal pathways, Ras/Raf/MEK1/2,\u0000PI3K/Akt, G-protein/PLC/PKC, Rho/Rock/NF-ĸB and PTEN; they are all related to cell growth, proliferation, differentiation, apoptosis, migration, and stress fiber formation. The SphK1/S1P signal pathway\u0000influences tumor cells' growth, proliferation, survival and angiogenesis, and SphK1 inhibitors can decrease Treg cell recruitment at tumor location. In T cells, SphK1/S1P signal way activates NF-ĸB and\u0000induces proliferator-activated receptor γ (PPARγ) transcription, which in turn regulates lipolysis in T\u0000cells. SphK1 can induce T cell failure through excessive S1P in extracellular vesicles of the tumor microenvironment. SphK1 inhibitors block S1P generation and inhibit cell growth, proliferation, differentiation,\u0000apoptosis, migration, and stress fiber formation, leading to increased CD8+T cells and decreased Treg\u0000cells in the tumor microenvironment. S1P also upregulates the expression of programmed cell death 1\u0000ligand 1(PD-L1) through Early 2-factor transcription factor 1 (E2F1).\u0000\u0000\u0000\u0000The discovery of better Sphk1 inhibitors by pharmacophore model, ADMET, molecular docking, MM/GBSA, and MD simulation.\u0000\u0000\u0000\u0000Here, SphK1 pharmacophore was created; first, it was used for virtual screening, ADMET properties of screened-out molecules were predicted, and the obtained molecules were performed molecular\u0000docking and Molecular Mechanics Generalized Born Surface Area (MM/GBSA) calculation, then molecular dynamics (MD) simulation was performed, and Molecular Mechanics Poisson-Boltzmann Surface\u0000Area (MM/PBSA) were calculated.\u0000\u0000\u0000\u0000Compounds 1, 2, and 3 were obtained through screening, and the binding energy of 1, 2, and 3\u0000were better than that of the existing corresponding target inhibitors.\u0000\u0000\u0000\u0000The overexpression of SphK1 is closely related to the occurrence, development,\u0000migration and drug resistance of tumors and has a good prospect of drug development. Given the\u0000important role of SphK1 inhibitors in treating tumors and the shortcomings of clinical application of\u0000SphK1 inhibitors, small molecule targeting inhibition SphK1 was screened to overcome the low\u0000efficiency. Firstly, estab-lishing a pharmacophore model for virtual screening, and then ADMET\u0000p","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design &amp; Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84637450","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":"Discovery of Natural Compounds As SARS-CoV-2’s Main Protease Inhibitors\u0000by Docking-based Virtual Screening","authors":"Hui Yu, Zhanli Wang, Jing Wang, Yu Jiang, Yingnan Wu, Yuheng Ma","doi":"10.2174/1570180820666230502152058","DOIUrl":"https://doi.org/10.2174/1570180820666230502152058","url":null,"abstract":"\u0000\u0000The novel coronavirus disease (COVID-19) is a viral disease caused by severe\u0000acute respiratory syndrome coronavirus 2 (SAR-CoV-2). The development of antiviral drugs has enhaced\u0000treatment of COVID-19. SARS-CoV-2 main protease (Mpro) is a key enzyme responsible for viral replication\u0000and transcription. This study aimed to identify new natural structures for the design of SARS-CoV-2\u0000Mpro inhibitors.\u0000\u0000\u0000\u0000In this present work, The CDOCKER protocol and scoring functions were validated. The validated\u0000docking-based virtual screening approach was then employed to search the in-house database of\u0000natural compounds for potential lead compounds as SARS-CoV-2 Mpro inhibitors. The top 3 compounds\u0000were further biologically evaluated in vitro.\u0000\u0000\u0000\u0000Docking studies of the known ligand GC-376 led to results consistent with cocrystallized\u0000data (PDB ID: 7D1M). Additionally, the effectiveness of docking scoring functions was validated\u0000by using the training set consisting of 15 active compounds and 15 inactive compounds. Then, the\u0000in-house database of natural compounds (overall 34,439 natural compounds) was subjected to dockingbased\u0000virtual screening resulting in the identification of the top 100 compounds having relatively better\u0000docking scores. Among them, the highest ranking 3 compounds (W-1, W-2, and W-3) were biologically\u0000evaluated in vitro for their inhibitory activity against SARS-CoV-2 Mpro, and compound W-1 was identified\u0000as the most potent SARS-CoV-2 Mpro inhibitor with an IC50 value of 63 ± 3 μM. Interestingly, it appeared\u0000that the in vitro activities of compounds W-1, W-2, and W-3 were in agreement with their molecular\u0000modeling data.\u0000\u0000\u0000\u0000Our results provided a useful reference for the discovery of novel natural SARS-CoV-2 Mpro\u0000inhibitors by virtual screening.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design &amp; Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83982379","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}