Current computer-aided drug design最新文献

{"title":"Identification of Kaempferol as Viral Entry Inhibitor and DL-Arginine as Viral Replication Inhibitor from Selected Plants of Indian Traditional Medicine against COVID-19: An <i>in silico</i> Guided in vitro Approach.","authors":"Adithya J,&nbsp;Maneesha Murali,&nbsp;Bhagyalakshmi Nair,&nbsp;Feby Benny,&nbsp;Rajalakshmi P M,&nbsp;Darshana Suresh,&nbsp;Aneesh T P,&nbsp;Amrutha Nisthul,&nbsp;Lekshmi R Nath","doi":"10.2174/1573409919666230112123213","DOIUrl":"https://doi.org/10.2174/1573409919666230112123213","url":null,"abstract":"<p><strong>Background: </strong>Indian traditional medicinal plants are known for their great potential in combating viral diseases. Previously, we reported a systematic review approach of seven plausible traditional Indian medicinal plants against SARS-CoV-2.</p><p><strong>Methods: </strong>Molecular docking was conducted with Biovia Discovery Studio. Three binding domains for spike glycoprotein (PDB IDs: 6LZG, 6M17, 6M0J) and one binding domain of RdRp (PDB ID: 7BTF) were used. Among 100 phytoconstituents listed from seven plants by the IMPPAT database used for virtual screening, the best six compounds were again filtered using Swiss ADME prediction and Lipinski's rule. Additionally, a pseudovirion assay was performed to study the interaction of SARS-CoV-2 S1-protein with the ACE 2 receptor to further confirm the effect.</p><p><strong>Results: </strong>Chebulagic acid (52.06 Kcal/mol) and kaempferol (48.84 Kcal/mol) showed increased interaction energy compared to umifenovir (33.68 Kcal/mol) for the 6LZG binding domain of spike glycoprotein. Epicatechin gallate (36.95 Kcal/mol) and arachidic acid (26.09 Kcal/mol) showed equally comparable interaction energy compared to umifenovir (38.20 Kcal/mol) for the 6M17 binding domain of spike glycoprotein. Trihydroxychalcone (35.23 Kcal/mol) and kaempferol (36.96 Kcal/mol) showed equally comparable interaction energy with umifenovir (36.60 Kcal/mol) for 6M0J binding domain of spike glycoprotein. Upon analyzing the phytoconstituents against RdRp binding domain, DL-arginine (41.78 Kcal/mol) showed comparable results with the positive control remdesivir (47.61 Kcal/mol). ADME analysis performed using Swiss ADME revealed that kaempferol and DL arginine showed drug-like properties with appropriate pharmacokinetic parameters. Further in vitro analysis of kaempferol by pseudovirion assay confirmed an acceptable decrease of the lentiviral particles in transfected HEK293T-hACE2 cells.</p><p><strong>Conclusion: </strong>The study highlights that kaempferol and DL-arginine could be the significant molecules to exhibit potent action against SARS-CoV-2 and its variants.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 4","pages":"313-323"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9547912","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":"Integrating Bioinformatics and Network Pharmacology to Explore the Therapeutic Target and Molecular Mechanisms of Schisandrin on Hypertrophic Cardiomyopathy.","authors":"Chaozhuang Shen,&nbsp;Pingping Shen,&nbsp;Xiaohu Wang,&nbsp;Xingwen Wang,&nbsp;Wenxin Shao,&nbsp;Kuo Geng,&nbsp;Haitang Xie","doi":"10.2174/1573409919666221124144713","DOIUrl":"https://doi.org/10.2174/1573409919666221124144713","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease and is currently the leading cause of sudden death in adolescent athletes. Schisandrin is a quality marker of the traditional Chinese medicine Schisandra chinensis, which has an excellent therapeutic effect on HCM, but its pharmacological mechanism remains unclear.</p><p><strong>Objective: </strong>This study aimed to explore the potential and provide scientific evidence for schisandrin as a lead compound against hypertrophic cardiomyopathy.</p><p><strong>Methods: </strong>The drug-like properties of schisandrin were predicted using the SwissADME website. Then, the PharmMapper database was used to predict potential drug targets and match gene names in the Uniprot database. HCM targets were collected from NCBI, OMIM, and Genecards databases and intersected with drug targets. The intersection targets were imported into the STRING database for PPI analysis, and core targets were identified. KEGG and GO enrichment analysis was performed on the core targets through the DAVID database, and all network maps were imported into Cytoscape software for visualization optimization. HCM-related datasets were downloaded from the GEO database to analyze core targets and screen differentially expressed target genes for molecular docking.</p><p><strong>Results: </strong>After the PPI network analysis of the intersection targets of drugs and diseases, 12 core targets were screened out. The KEGG analysis results showed that they were mainly involved in Rap1, TNF, FoxO, PI3K-Akt, and other signaling pathways. After differential analysis, PPARG, EGFR, and MMP3 targets were also screened. The molecular docking results showed that schisandrin was well bound to the protein backbone of each target.</p><p><strong>Conclusion: </strong>This study used network pharmacology combined with differential expression and molecular docking to predict that schisandrin may treat HCM by acting on PPARG, EGFR, and MMP3 targets, and the regulatory process may involve signaling pathways, such as Rap1, TNF, FoxO, and PI3K-Akt, which may provide a valuable reference for subsequent studies.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 3","pages":"192-201"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9465702","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":"Hydroxycoumarins and some Flavonoids from <i>Pistacia atlantica</i> Desf. as Multi-targets Inhibitors for Alzheimer's Disease: Molecular Docking and ADMET Studies.","authors":"Meriem Lamrani,&nbsp;Talia Serseg,&nbsp;Khedidja Benarous,&nbsp;Ibrahim Sifi,&nbsp;Mohamed Yousfi","doi":"10.2174/1573409919666221104093218","DOIUrl":"https://doi.org/10.2174/1573409919666221104093218","url":null,"abstract":"<p><strong>Objective: </strong>The present study aimed to identify new selective inhibitors for acetylcholinesterase, butyrylcholinesterase, monoacylglycerol lipase, beta-secretase, and Asparagine endopeptidase, the targets enzymes in Alzheimer's disease.</p><p><strong>Methods: </strong>The inhibitory effect of P. atlantica Desf. methanol extracts against AChE were determined using Ellman's method. The molecular docking study is achieved using Autodock Vina. The structures of the molecules 3-methoxycarpachromene, masticadienonic acid, 7-ethoxycoumarin, 3',5,7- trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol-3-O-rutinoside and the five enzymes were obtained from the PubChem database and Protein databank. ADMET parameters were checked to confirm their pharmacokinetics using swiss-ADME and ADMET-SAR servers.</p><p><strong>Results: </strong>P. atlantica Desf. methanol extracts showed a notable inhibitory effect against AChE (IC₅₀ = 0.26 ± 0.004 mg/ml). The molecular docking results of 3-methoxycarpachromene, masticadienonic acid, 7-ethoxycoumarin, 3',5,7-trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol-3-Orutinoside with the five enzymes show significant affinities of these molecules towards Alzheimer disease targets, where they could form several interactions, such as hydrogen bonds and hydrophobic interactions with the studied enzymes. The shortest hydrogen bond is 1.7 A° between masticadienonic acid and Arg128 of the active site of BACE, while the lowest free energy is -11.2 of the complex 5,6,7,4'-tetrahydroxyflavonol-3-O-rutinoside -HuBchE. To the best of our knowledge, these molecules' potential anti-Alzheimer disease effect is studied in this paper for the first time.</p><p><strong>Conclusion: </strong>The docking studies of this work show that 3-methoxycarpachromene and masticadienonic acid, 7-ethoxycoumarin, 3',5,7-Trihydroxy-4'-methoxyflavanone and 5,6,7,4'-tetrahydroxyflavonol- 3-O-rutinoside have good affinities towards the enzymes involved in Alzheimer pathology, which confirm the ability of these molecules to inhibit the studied enzymes namely: HuAChE, HuBChE, BACE, MAGL, and AEP. These molecules might become drug candidates to prevent Alzheimer's disease.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 3","pages":"176-191"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9469264","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":"Bioactive Phytochemicals and Molecular Mechanisms of <i>Artemisiae capillariae</i> against Drug Induced Liver Injury based on Network Pharmacology.","authors":"Wen Shan,&nbsp;Zhiping Yang,&nbsp;Junzi Huang,&nbsp;Musen Lin,&nbsp;Yan Zhao,&nbsp;Yan Hu,&nbsp;Ran Yan,&nbsp;Xi Wu","doi":"10.2174/1573409919666230301092720","DOIUrl":"https://doi.org/10.2174/1573409919666230301092720","url":null,"abstract":"<p><strong>Background: </strong>Artemisiae capillariae (Yinchen, YC) is a well-known herbal medicine used to treat drug-induced liver diseases, while the bioactive phytochemicals and pharmacological targets of YC remain unclear.</p><p><strong>Objective: </strong>The study aimed to probe the key active components in YC and determine the potential molecular mechanisms of YC protect against DILI.</p><p><strong>Methods: </strong>In this study, we first delved into the active chemicals and targets of YC, identified potential anti-AILI targets for YC, mapped the components-targets network, performed proteinprotein interaction (PPI) analysis, gene ontology (GO) enrichment, and Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway analyses of the action targets. This led to figure out the liver protective mechanism of YC against AILI. Analyzing the molecular docking of key targets, binding domain of ingredients and targets reveals the effective interaction, and the binding energy explains the efficiency and stability of the interactions.</p><p><strong>Results: </strong>Network analysis identified 53 components in YC; by systematic screening 13 compounds were selected, which were associated with 123 AILI-related genes. The core ingredients were quercetin, capillarisin and Skrofulein, and the identified crucial genes were AKT1, TNF, and IL6. The GO and KEGG pathway enrichment analysis results indicated that the anti-AILI targets of YC mainly take a part in the regulation of oxidative stress and immune, with related signaling pathways including PI3K/AKT and IL17. Furthermore, the binding pockets of YC bioactive ingredients and key targets were revealed, and the binding ability was proved by molecular docking analysis.</p><p><strong>Conclusion: </strong>This study has revealed the potential bioactive molecules and mechanism of YC in AILI and provided a possible strategy for the identification of active phytochemicals against druginduced liver injury.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 6","pages":"476-489"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9474040","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":"Identification of Novel Peptides as Potential Modulators of Aβ42 Amyloidogenesis: An <i>in silico</i> Approach.","authors":"Kavita Kundal,&nbsp;Santhosh Paramasivam,&nbsp;Amit Mitra,&nbsp;Nandini Sarkar","doi":"10.2174/1573409919666230112170012","DOIUrl":"https://doi.org/10.2174/1573409919666230112170012","url":null,"abstract":"<p><strong>Aims: </strong>Alzheimer's disease is a neurodegenerative disease for which no cure is available. The presence of amyloid plaques in the extracellular space of neural cells is the key feature of this fatal disease.</p><p><strong>Background: </strong>The proteolysis of Amyloid Precursor Protein by presenilin leads to the formation of Amyloid-beta peptides (Aβ 42/40). Deposition of 42 residual Aβ peptides forms fibril's structure, disrupting neuron synaptic transmission, inducing neural cell toxicity, and ultimately leading to neuron death.</p><p><strong>Objective: </strong>Various novel peptides have been investigated via molecular docking and molecular dynamic simulation studies to investigate their effects on Aβ amyloidogenesis.</p><p><strong>Methods: </strong>The sequence-based peptides were rationally designed and investigated for their interaction with Aβ42 monomer and fibril, and their influence on the structural stability of target proteins was studied.</p><p><strong>Results: </strong>Analyzed docking results suggest that the peptide YRIGY (P6) has the highest binding affinity with Aβ42 fibril amongst all the synthetic peptides, and the peptide DKAPFF (P12) similarly shows a better binding with the Aβ42 monomer. Moreover, simulation results also suggest that the higher the binding affinity, the better the inhibitory action.</p><p><strong>Conclusion: </strong>These findings indicate that both the rationally designed peptides can modulate amyloidogenesis, but peptide (P6) has better potential for the disaggregation of the fibrils. In contrast, peptide P12 stabilizes the native structure of the Aβ42 monomer more effectively and hence can serve as a potential amyloid inhibitor. Thus, these peptides can be explored as therapeutic agents against Alzheimer's disease. Experimental testing of these peptides for immunogenicity, stability in cellular conditions, toxic effects and membrane permeability can be the future research scope of this study.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 4","pages":"288-299"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9542014","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":"Molecular Docking, ADMET Analysis and Molecular Dynamics (MD) Simulation to Identify Synthetic Isoquinolines as Potential Inhibitors of SARS-CoV-2 M^PRO.","authors":"Paulo Ricardo Dos Santos Correia,&nbsp;Alesson Henrique Donato de Souza,&nbsp;Andres Reyes Chaparro,&nbsp;Aldo Yair Tenorio Barajas,&nbsp;Ricardo Silva Porto","doi":"10.2174/1573409919666230123150013","DOIUrl":"https://doi.org/10.2174/1573409919666230123150013","url":null,"abstract":"<p><strong>Background: </strong>The rapidly widespread SARS-CoV-2 infection has affected millions worldwide, thus becoming a global health emergency. Although vaccines are already available, there are still new COVID-19 cases daily worldwide, mainly due to low immunization coverage and the advent of new strains. Therefore, there is an utmost need for the discovery of lead compounds to treat COVID-19.</p><p><strong>Objective: </strong>Considering the relevance of the SARS-CoV-2 M^PRO in viral replication and the role of the isoquinoline moiety as a core part of several biologically relevant compounds, this study aimed to identify isoquinoline-based molecules as new drug-like compounds, aiming to develop an effective coronavirus inhibitor.</p><p><strong>Methods: </strong>274 isoquinoline derivatives were submitted to molecular docking interactions with SARS-CoV-2 M^PRO (PDB ID: 7L0D) and drug-likeness analysis. The five best-docked isoquinoline derivatives that did not violate any of Lipinski's or Veber's parameters were submitted to ADMET analysis and molecular dynamics (MD) simulations.</p><p><strong>Results: </strong>The selected compounds exhibited docking scores similar to or better than chloroquine and other isoquinolines previously reported. The fact that the compounds interact with residues that are pivotal for the enzyme's catalytic activity, and show the potential to be orally administered makes them promising drugs for treating COVID-19.</p><p><strong>Conclusion: </strong>Ultimately, MD simulation was performed to verify ligand-protein complex stability during the simulation period.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 5","pages":"391-404"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9842748","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":"Natural Metabolite Ursolic Acid as an Inhibitor of Dormancy Regulator DosR of <i>Mycobacterium tuberculosis</i>: Evidence from Molecular Docking, Molecular Dynamics Simulation and Free Energy Analysis.","authors":"Babban Jee, Prem Prakash Sharma, Vijay Kumar Goel, Sanjay Kumar, Yogesh Singh, Brijesh Rathi","doi":"10.2174/1573409919666230201100543","DOIUrl":"10.2174/1573409919666230201100543","url":null,"abstract":"<p><strong>Background: </strong>DosR is a transcriptional regulator of Mycobacterium tuberculosis</i> (MTB), governing the expression of a set of nearly 50 genes that is often referred to as 'dormancy regulon'. The inhibition of DosR expression by an appropriate inhibitor may be a crucial step against MTB.</p><p><strong>Objective: </strong>We targeted the DosR with natural metabolites, ursolic acid (UA) and carvacrol (CV), using in silico</i> approaches.</p><p><strong>Methods: </strong>The molecular docking, molecular dynamics (MD) simulation for 200 ns, calculation of binding energies by MM-GBSA method, and ADMET calculation were performed to evaluate the inhibitory potential of natural metabolites ursolic acid (UA) and carvacrol (CV) against DosR of MTB.</p><p><strong>Results: </strong>Our study demonstrated that UA displayed significant compatibility with DosR during the 200 ns timeframe of MD simulation. The thermodynamic binding energies by MM-GBSA also suggested UA conformational stability within the binding pocket. The SwissADME, pkCSM, and OSIRIS DataWarrior showed a drug-likeness profile of UA, where Lipinski profile was satisfied with one violation (MogP > 4.15) with no toxicities, no mutagenicity, no reproductive effect, and no irritant nature.</p><p><strong>Conclusion: </strong>The present study suggests that UA has the potency to inhibit the DosR expression and warrants further investigation on harnessing its clinical potential.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 6","pages":"425-437"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9842762","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":"Identification of Small Inhibitors for Human Metadherin, an Oncoprotein, through <i>in silico</i> Approach.","authors":"Arif Ali Khattak,&nbsp;Ayaz Ahmad,&nbsp;Haider Ali Khattak,&nbsp;Muhammad Zafar Irshad Khan","doi":"10.2174/1573409919666230110112356","DOIUrl":"https://doi.org/10.2174/1573409919666230110112356","url":null,"abstract":"<p><strong>Aims: </strong>Cancer is a disease that takes lives of thousands of people each year. There are more than 100 different types of cancers known to man. This fatal disease is one of the leading causes of death today.</p><p><strong>Background: </strong>Astrocyte elevated gene-1(AEG-1)/Metadherin (MTDH) activates multiple oncogenic signaling pathways and leads to different types of cancers. MTDH interacting with staphylococcal nuclease domain containing 1(SND1) supports the survival and growth of mammary epithelial cells under oncogenic conditions.</p><p><strong>Objective: </strong>Silencing MTDH or SND1 individually or disrupting their interaction compromises the tumorigenic potential of tumor-initiating cells. The aim of our present study was to investigate novel interactions of staphylococcal nuclease domain containing 1 (SND1) binding domain of AEG-1/MTDH with different lead compounds through molecular docking approach using MOE software.</p><p><strong>Methods: </strong>Molecular docking was done by docking the ChemBridge database against important residues of MTDH involved in interaction with SND1. After docking the whole ChemBridge database, the top 200 interactive compounds were selected based on docking scores. After applying Lipinski's rule, all the remaining chosen compounds were studied on the basis of binding affinity, binding energy, docking score and protein-ligand interactions. Finally, 10 compounds showing multiple interactions with different amino acid residues were selected as the top interacting compounds.</p><p><strong>Results: </strong>Three compounds were selected for simulation studies after testing these compounds using topkat toxicity and ADMET studies. The simulation study indicated that compound 32538601 is a lead compound for inhibiting MTDH-SND1 complex formation.</p><p><strong>Conclusion: </strong>These novels, potent inhibitors of MTDH-SND1 complex can ultimately help us in controlling cancer up to some extent.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 4","pages":"278-287"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9550063","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":"The Custom R Group Enumeration with Various R Group Libraries at Designated Sites on Amphotericin B.","authors":"Ajay Mahor,&nbsp;Devesh M Sawant,&nbsp;Amit K Goyal","doi":"10.2174/1573409919666230123144712","DOIUrl":"https://doi.org/10.2174/1573409919666230123144712","url":null,"abstract":"<p><strong>Background: </strong>Amphotericin B is a gold-standard drug, particularly for the treatment of systemic fungal infections. However, its low solubility and permeability limit its application. To improve its bioavailability, AmB may be conjugated with various water-soluble auxiliary groups.</p><p><strong>Methods: </strong>Custom R group Enumeration was used at the designated sites of Amphotericin B. The designated sites taken into consideration are the carboxyl moiety of the aglycone part and the amine moiety of the glycone part of Amphotericin B for Enumeration purposes. The enumerated molecules were subjected to QikProp properties.</p><p><strong>Results: </strong>We identified fourteen hits with improved predicted aqueous solubility and cell permeability.</p><p><strong>Conclusion: </strong>Enumeration might be applicable in improving bioavailability, which could lead to the oral formulation of the Amphotericin B drug.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 5","pages":"382-390"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9472242","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, 'ADMET-SAR' Prediction, DPPH Assay, and Anti-Mycobacterium Study of 4-[(substituted benzyl) amino]benzo hydrazides and its Hydrazones as the Acyl-CoA Carboxylase, AccD5 Inhibitors.","authors":"Vijay J Desale,&nbsp;Suraj N Mali,&nbsp;Bapu R Thorat,&nbsp;Ramesh S Yamgar,&nbsp;Swapnali V Dharanguttikar,&nbsp;Vyankatesh R Dharanguttikar,&nbsp;Samir Chtita,&nbsp;Mozaniel Oliveira,&nbsp;Jorddy Neves Cruz","doi":"10.2174/1573409919666221227091735","DOIUrl":"https://doi.org/10.2174/1573409919666221227091735","url":null,"abstract":"<p><strong>Background: </strong>Hydrazide-hydrazone derivatives have shown diverse biological activities, such as antitubercular (anti-TB), antibacterial, antifungal, anticancer, anti-inflammatory, antiviral, and antiprotozoal actions.</p><p><strong>Objectives: </strong>Hydrazide-hydrazones contain azomethine (-NH-N=CH-) group connected with carbonyl group and are believed to be responsible for various pharmaceutical applications. They aid in the synthesis of different five-membered heterocyclic systems, such as oxadiazole, triazoles, etc. Methods: In the present study, various hydrazines/hydrazones were synthesized starting from 4- amino benzoic acid derivatives. Structures of all 9 newly synthesized compounds (6a-6d and 8a- 8e) were further characterized by using various spectroscopic methods, such as ¹H-NMR (Nuclear Magnetic Resonance), FT-IR (Fourier-transform infrared spectroscopy), Gas chromatographymass spectrometry (GC-MS), etc. Furthermore, molecular docking analysis against the acyl-CoA carboxylase, AccD5 (PDB ID: 2A7S), was also carried out using the Glide module, which depicted good binding scores than standard drugs. The anti-tuberculosis activity of all the hydrazides and hydrazones (6a-6d and 8a-8e) were evaluated against the Mycobacterium tuberculosis H37 RV strain using the Alamar-Blue susceptibility (MABA) test. The activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL values. The antioxidant activity was also carried out using a DPPH assay.</p><p><strong>Results: </strong>Our findings demonstrated highly encouraging in-vitro results (MABA assay, MIC: 1.2 μg/mL) of hydrazones as depicted by good antimycobacterial activity. The antioxidant results showed a moderate to a good percentage of DPPH inhibition. Our in-silico ADMET analysis further suggested good pharmacokinetic and toxicity-free profiles of synthesized analogues (<i>6a-6d</i> and <i>8a-8e</i>).</p><p><strong>Conclusion: </strong>Our results signify hydrazones/hydrazines as potential hit candidates against the future developments of potent and safer anti-TB agents.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 4","pages":"300-312"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9553484","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}