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Novel ligand-based docking;molecular dynamic simulations;and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease

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Journal of Pharmaceutical Analysis 2018年第6期8卷 413-420页

作者： Subramaniyan Vijayakumar Palani Manogar Srinivasan Prabhu Ram Avadhar Sanjeevkumar Singh Computational Phytochemistry Laboratory PG and Research Department of Botany and Microbiology AVVM Sri Pushpam College (Autonomous) Poondi Computer Aided Drug Design and Molecular Modeling Laboratory Department of Bioinformatics Alagappa University

Acetylcholinesterase(AChE) plays an important role in Alzheimer's disease(AD). The excessive activity of AChE causes various neuronal problems, particularly dementia and neuronal cell deaths. Generally, antiAChE drugs induce some serious neuronal side effects in humans. Therefore, this study sought to identify alternative drug molecules from natural products with fewer side effects than those of conventional drugs for treating AD. To achieve this, we developed computational methods for predicting drug and target binding affinities using the Schrodinger suite. The target and ligand molecules were retrieved from established databases. The target enzyme has 539 amino acid residues in its sequence alignment. Ligand molecules of 20 bioactive molecules were obtained from different kinds of plants, after which we performed critical analyses such as molecular docking; molecular dynamic(MD) simulations; and absorption, distribution, metabolism, and excretion(ADME) analysis. In the docking studies, the natural compound rutin showed a superior docking score of à 12.335 with a good binding energy value ofà73.313 kcal/mol. Based on these findings, rutin and the target complex was used to perform MD simulations to analyze rutin stability at 30 ns. In conclusion, our study demonstrates that rutin is a superior drug candidate for AD. Therefore, we propose that this molecule is worth further investigation using in vitro studies.

关键词： Alzheimer's disease Acetylcholinesterase Phytocompounds molecular docking Free energy calculations molecular dynamic simulations

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molecular characterization of Lipopeptide Biosurfactant-Producing Paenibacillus dendritiformis isolated from Brackish water and its Potential Use in Microbial Enhanced Oil Recovery and Bioremediation

Research Square

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Research Square 2021年

作者： Nayarisseri, Anuraj Bhrdwaj, Anushka Sharma, Khushboo Khan, Arshiya Singh, Sanjeev Kumar In Silico Research Laboratory Eminent Biosciences Madhya Pradesh Indore452 010 India Bioinformatics Research Laboratory LeGene Biosciences Pvt Ltd Madhya Pradesh Indore452010 India Computer Aided Drug Designing and Molecular Modeling Lab Department of Bioinformatics Alagappa University Tamil Nadu Karaikudi630 003 India Department of Data Sciences Centre of Biomedical Research SGPGIMS Campus 13 Raebareli Rd Lucknow226014 India

The biosurfactants produced by microorganisms have a high demand for microbial-enhanced oil recovery (MEOR) and they have focused on a chemical surfactant for the past few decades for degrading petro-based pollutants and oil spills due to its non-toxicity and increasing bioavailability. The study aims to identify and screen potential lipopeptide biosurfactants produced by Paenibacillus species employing a design experiment based on RSM. The bacterial culture was isolated from Chilika Lake, India. The data generated from the biosurfactant stability experiments were used to fit a regression model using the parameters such as pH, temperature, and salinity to predict the E24 index. The R-squared value 0.91 obtained from the ANOVA model explains that the regression model was significant, and the model p-value obtained was © 2021, CC BY.

关键词： Phylogenetic

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Structure-based virtual screening toward the discovery of novel inhibitors for impeding the protein-protein interaction between HIV-1 integrase and human lens epithelium-derived growth factor (LEDGF/p75)

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Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2018年第12期36卷 3199-3217页

作者： Panwar Singh S a Computer Aided Drug Design and Molecular Modelling Lab Department of Bioinformatics Alagappa University Karaikudi 630004 Tamil Nadu India

HIV-1 integrase is a unique promising component of the viral replication cycle, catalyzing the integration of reverse transcribed viral cDNA into the host cell genome. Generally, IN activity requires both viral as well as a cellular co-factor in the processing replication cycle. Among them, the human lens epithelium-derived growth factor (LEDGF/p75) represented as promising cellular co-factor which supports the viral replication by tethering IN to the chromatin. Due to its major importance in the early steps of HIV replication, the interaction between IN and LEDGF/p75 has become a pleasing target for anti-HIV drug discovery. The present study involves the finding of novel inhibitor based on the information of dimeric CCD of IN in complex with known inhibitor, which were carried out by applying a structure-based virtual screening concept with molecular docking. Additionally, Free binding energy, ADME properties, PAINS analysis, Density Functional Theory, and Enrichment Calculations were performed on selected compounds for getting a best lead molecule. On the basis of these analyses, the current study proposes top 3 compounds: Enamine-Z742267384, Maybridge-HTS02400, and Specs-AE-848/37125099 with acceptable pharmacological properties and enhanced binding affinity to inhibit the interaction between IN and LEDGF/p75. Furthermore, Simulation studies were carried out on these molecules to expose their dynamics behavior and stability. We expect that the findings obtained here could be future therapeutic agents and may provide an outline for the experimental studies to stimulate the innovative strategy for research community.

关键词： ADME – Absorption, Distribution, Metabolism, Excretion AIDS AIDS – Acquired immunodeficiency syndrome CCD – catalytic core domain CNS – Central Nervous System DFT – Density Functional Theory HIV-1 integrase IBD – IN-binding domain IFD – Induced fit docking IN – Integrase LEDGF/p75 – lens epithelium-derived growth factor LEDGINs – lens epithelium-derived growth factor Integrase Inhibitor MDS – molecular dynamics simulation MM-GBSA – molecular Mechanics energies combined with the Generalized Born and Surface Area continuum solvation PPI – protein-protein interaction VS – Virtual screening human LEDGF/p75 molecular docking and simulation protein–protein interaction virtual screening

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Weak-binding molecules are not drugs?-toward a systematic strategy for finding effective weak-binding drugs

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BRIEFINGS IN BIOINFORMATICS 2017年第2期18卷 321-332页

作者： Wang, Jinan Guo, Zihu Fu, Yingxue Wu, Ziyin Huang, Chao Zheng, Chunli Shar, Piar Ali Wang, Zhenzhong Xiao, Wei Wang, Yonghua Northwest A&F Univ Ctr Bioinformat Coll Life Sci Computer Aided Drug Design & TCM Syst Pharmacol Xianyang Shaanxi Peoples R China Northwest A&F Univ Ctr Bioinformat Coll Life SciModeling Signal Pathway Complex Dis TCM Syst Pharmacol & Machine Learning Xianyang Shaanxi Peoples R China Northwest A&F Univ Ctr Bioinformat Coll Life Sci Syst PharmacolNetwork Med & Computat Biol Xianyang Shaanxi Peoples R China Northwest A&F Univ Ctr Bioinformat Coll Life Sci TCM Syst PharmacolCell Regulat & Signal Transduc Xianyang Shaanxi Peoples R China Northwest A&F Univ Ctr Bioinformat Coll Life Sci Network BiolTCM Syst Pharmacol Xianyang Shaanxi Peoples R China Northwest A&F Univ Ctr Bioinformat Coll Life Sci Machine LearningTCM Syst Pharmacol Xianyang Shaanxi Peoples R China Kanion Pharmaceut Co Ltd Chinese Med Pharmaceut Proc State Key Lab New Tech R&D Director Lianyungang Peoples R China New Tech Chinese Med Qual Control New Extracting Tech Chinese Med Lianyungang Peoples R China Kanion Pharmaceut Co Ltd Chinese Med Pharmaceut Proc State Key Lab New Tech Lianyungang Peoples R China New Tech Chinese Med Qual control New Extracting Tech Chinese Med Lianyungang Peoples R China Northwest A&F Univ Ctr Bioinformat Coll Life Sci Xianyang Shaanxi Peoples R China ADME Properties Drug Mol TCM Syst Pharmacol Network Biol Xianyang Shaanxi Peoples R China Northwest A&F Univ Coll Life Sci Ctr Bioinformat Lab Syst Pharmacol Yangling 712100 Shaanxi Peoples R China

designing maximally selective ligands that act on individual drug targets with high binding affinity has been the central dogma of drug discovery and development for the past two decades. However, many low-affinity drugs that aim for several targets at the same time are found more effective than the high-affinity binders when faced with complex disease conditions, such as cancers, Alzheimer's disease and cardiovascular diseases. The aim of this study was to appreciate the importance and reveal the features of weak-binding drugs and propose an integrated strategy for discovering them. Weak-binding drugs can be characterized by their high dissociation rates and transient interactions with their targets. In addition, network topologies and dynamics parameters involved in the targets of weak-binding drugs also influence the effects of the drugs. Here, we first performed a dynamics analysis for 33 elementary subgraphs to determine the desirable topology and dynamics parameters among targets. Then, by applying the elementary subgraphs to the mitogen-activated protein kinase (MAPK) pathway, several optimal target combinations were obtained. Combining drug-target interaction prediction with molecular dynamics simulation, we got two potential weak-binding drug candidates, luteolin and tanshinone IIA, acting on these targets. Further, the binding affinity of these two compounds to their targets and the anti-inflammatory effects of them were validated through in vitro experiments. In conclusion, weak-binding drugs have real opportunities for maximum efficiency and may show reduced adverse reactions, which can offer a bright and promising future for new drug discovery.

关键词： weak-binding drug polypharmacology mathematical modeling systems pharmacology

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Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27^KIP1-derived peptidomimetic inhibitors

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Journal of Chemical Biology 2015年第1期8卷 11-24页

作者： Karthiga, Arumugasamy Tripathi, Sunil Kumar Shanmugam, Ramasamy Suryanarayanan, Venkatesan Singh, Sanjeev Kumar Computer Aided Drug Designing and Molecular Modeling Lab Department of Bioinformatics Alagappa University Karaikudi 630 003 Tamil Nadu India Department of Chemistry Thiagarajar College Madurai 625009 Tamil Nadu India

Functionally activated cyclin-dependent kinase 2 (CDK2)/cyclin A complex has been validated as an interesting therapeutic target to develop the efficient antineoplastic drug based on the cell cycle arrest. Cyclin A binds to CDK2 and activates the kinases as well as recruits the substrate and inhibitors using a hydrophobic cyclin-binding groove (CBG). Blocking the cyclin substrate recruitment on CBG is an alternative approach to override the specificity hurdle of the currently available ATP site targeting CDK2 inhibitors. Greater understanding of the interaction of CDK2/cyclin A complex with p27 (negative regulator) reveals that the Leu-Phe-Gly (LFG) motif region of p27 binds with the CBG site of cyclin A to arrest the malignant cell proliferation that induces apoptosis. In the present study, Replacement with Partial Ligand Alternatives through Computational Enrichment (REPLACE) drug design strategies have been applied to acquire LFG peptide-derived peptidomimetics library. The peptidomimetics function is equivalent with respect to substrate p27 protein fashion but does not act as an ATP antagonist. The combined approach of molecular docking, molecular dynamics (MD), and molecular electrostatic potential and ADME/T prediction were carried out to evaluate the peptidomimetics. Resultant interaction and electrostatic potential maps suggested that smaller substituent is desirable at the position of phenyl ring to interact with Trp217, Arg250, and Gln254 residues in the active site. The best docked poses were refined by the MD simulations which resulted in conformational changes. After equilibration, the structure of the peptidomimetic and receptor complex was stable. The results revealed that the various substrate protein-derived peptidomimetics could serve as perfect leads against CDK2 protein. © 2014, Springer-Verlag Berlin Heidelberg.

关键词： Cyclin-binding groove MD simulation molecular docking Peptidomimetic inhibitor Protein–protein interaction

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182 molecular recognition between active site contour maps and ligand pharmacophoric sites predicts the future leads of HTLV-PR inhibitors

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Journal of Biomolecular Structure and Dynamics 2015年第SUPP 1期33卷 120页

作者： Sanjeev Kumar Singh[a][*] Chandrabose Selvaraj[a] [a] Computer Aided Drug Design and Molecular Modeling Lab Department of Bioinformatics Science Block Alagappa University Karaikudi 630004 Tamilnadu India

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11th German Conference on Chemoinformatics (GCC 2015) Abstracts

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JOURNAL OF CHEMINFORMATICS 2016年第SUPPL 1期8卷 1-27页

作者： [Anonymous] GDCh-CIC Division Associated Board Member Beilstein-Institut zur Förderung der Chemischen Wissenschaften Trakehner Str. 7-9 60487 Frankfurt Germany. ufechner@beilstein-institut.de. Division Medicinal Chemistry Amsterdam Institute for Molecules Medicines and Systems (AIMMS) VU University Amsterdam The Netherlands. Centre for Bioinformatics Uni Hamburg Bundesstr. 43 20146 Hamburg Germany. Sanofi-Aventis Deutschland GmbH 65926 Frankfurt am Main Germany. stefan.guessregen@***. Sanofi-Aventis Deutschland GmbH 65926 Frankfurt am Main Germany. GlaxoSmithKline Stevenage SG1 2NY UK. nicola.j.richmond@***. Discngine Paris 75011 France. Organisch-Chemisches Institut Westfälische Wilhelms-Universität Münster Germany. marwin.segler@wwu.de. Organisch-Chemisches Institut Westfälische Wilhelms-Universität Münster Germany. Bundeskriminalamt Wiesbaden Central Analytics II 65173 Wiesbaden Germany. Department of Chemistry and Biochemistry University of California Santa Barbara CA 93111 USA. shea@chem.ucsb.edu. Department of Chemistry and Biochemistry University of California Santa Barbara CA 93111 USA. Chemistry Department Ludwig-Maximilians-Universität München Butenandtstr. 7 81377 Munich Germany. Inorganic Chemistry and Center for Nanointegration University of Duisburg-Essen Essen Germany. CAM-D Technologies Essen Germany. Institute for Bioinformatics and Chemoinformatics Westphalian University of Applied Sciences Recklinghausen Germany. Institute for Bioinformatics and Chemoinformatics Westphalian University of Applied Sciences Recklinghausen Germany. achim.zielesny@w-hs.de. Leiden University Leiden Netherlands. j.fraaije@chem.leidenuniv.nl. Culgi BV Berlin Germany. Physikalische Chemie III TU Dortmund 44227 Dortmund Germany. stefan.kast@tu-dortmund.de. Centre for Molecular Informatics Department of Chemistry University of Cambridge Lensfield Road Cambridge CB2 1EW United Kingdom. kcb27@cam.ac.uk. Centre for Molecular Informatics Department of Chemistry

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186 molecular dynamics and ligand based studies for the validation of potential inhibitors for SrtA againstBacillus anthracis

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Journal of Biomolecular Structure and Dynamics 2013年第SUPP 1期31卷 119-120页

作者： Sanjeev Kumar Singh[a][*] & Chandrabose Selvaraj[a] [a] Computer Aided Drug Design and Molecular Modeling Lab Department of Bioinformatics Alagappa University Karaikudi 630003 India Phone: Phone: +91-4565-230725 Fax: Phone: +91-4565-230725

SrtA enzymes cleave the sorting signals of secreted proteins to form isopeptide (amide) bonds between the secreted proteins and peptidoglycan or polypeptides to function as the principal architects of theBacillus anthracis. Inhibition of SrtA can completely eradicate the growth ofB. anthracisdue to the lack of signals and so the SrtA is universally accepted as the drug target for all gram positive pathogens. Here, with the reported compounds, the pharmacophore-based virtual screening protocol has been used to obtain similar pharmacological property that derived new compounds to inhibit the SrtA structure. New compounds on AAAHR Pharmacophore hypothesis screening were treated with four phase of docking protocols with combined Glide-QPLD docking approach and charge accuracy variations were dominated by QM/MM approach. Finally, the compounds of 19941, 14704, 121962, 20137, and 19533 from binding db, Chembridge db, and Toslab were succeeded from the screening; these compounds are having better scoring, energy parameters, ADME physio/chemical properties, tendency to transfer the electrons between the protein–ligand interactions, and these compounds also predict having cell adhesion inhibitory activity. These screened compounds have better stability at active site loop regions with strong bonding interactions and these compounds on clinical trials will definitely emerge as better SrtA inhibitor against theB. anthracis.

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195In silicostudy on HIV-PRIs substructures to terminate proteolytic activity in HTLV

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Journal of Biomolecular Structure and Dynamics 2013年第SUPP 1期31卷 127页

作者： Poonam Singh[a][*] Sanjeev Kumar Singh[b] Chandrabose Selvaraj[b] & Rama Kant Singh[a] [a] Toxicology Division Central Drug Research Institute Lucknow 226 001 Uttar Pradesh India Phone: Phone: +91-522-2612411 Fax: Phone: +91-522-2612411 [b] Computer Aided Drug Design and Molecular Modeling Lab Department of Bioinformatics Alagappa University Karaikudi 630003 Tamilnadu India

Human T-lymphotropic virus (HTLV) is RNA retrovirus, which causes CD3 + and CD4 + T-cell type leukemia and demyelinating diseases, like tropical spastic myelopathy. The replicative stage of the virus is one of the critical stages for the development of the disease. At present, there are no approved therapeutic agents targeting HTLV. The HTLV mechanism of malignant cell growth in adult T-cell leukemia (ATL)/lymphoma, and the HTLV-PR has been an attractive target for anticancer drug design. In comparison with other retroviruses, HTLV also encodes protease (PR) enzyme which is essential for maturation. Both the HIV and HTLV proteases show high structural similarity but known inhibitors of HIV-PR are not able to inhibit the HTLV-PR, while comparing the binding pocket of both proteases, MET37 of HTLV shows repulsive role with known HIV inhibitors. Functional analysis of M37A mutation clearly shows that MET37 is highly important for the protease function. Available inhibitors were tested against the HTLV-PR binding pocket and failed to interact with MET37. Screening of similar libraries of known compounds provides better interactions with MET37 and further validation within vivoandin vitrostudies on these screened compounds will provide more strength in discovering potent inhibitor for HTLV-PR.

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