Faculty Publications

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    Design, synthesis and docking studies of quinoline-oxazolidinone hybrid molecules and their antitubercular properties
    (2011) Thomas, K.D.; Vasudeva Adhikari, A.V.; Chowdhury, I.H.; Sandeep, T.; Mahmood, R.; Bhattacharya, B.; Sumesh, E.
    New series of quinoline-oxazolidinone hybrid molecules were synthesized based on the preliminary docking studies. All the newly synthesized compounds were characterized by spectral analyses. The newly synthesized compounds were screened for their antimycobacterial properties based on the promising preliminary antibacterial screening results. Amongst tested compounds, compounds 8a, 8j and 13a were active at 0.65 ?g/mL against Mycobacterium tuberculosis H 37Rv strain. The mode of action of these active compounds was carried out by docking of receptor enoyl-ACP reductase with newly synthesized candidate ligands 8a, 8j and 13a. These compounds exhibited well established bonds with one or more amino acids in the receptor active pocket. From the docking studies, compound 8j was considered to be the best inhibitor. © 2011 Elsevier Masson SAS. All rights reserved.
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    Synthesis and anti-inflammatory evaluation of some new 3,6-disubstituted-1, 2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles bearing pyrazole moiety
    (2012) Malladi, S.; Isloor, A.M.; Shetty, P.; Fun, H.-K.; Telkar, S.; Mahmood, R.; Isloor, N.
    In the present study, a new series of 3,6-disubstituted- 1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles (4aj) have been synthesized by condensing 3-substituted-4-amino-5- mercapto-1,2,4-triazoles (1a-b) with various 3-substitutedpyrazole- 4-carboxylic acids (3a-e) in the presence ofPOCl3. The structures of newly synthesized compounds were characterized by elemental analysis, IR, 1H NMR, 13CNMR, and mass spectroscopic studies. Structure of the compound 4b was also confirmed by recording the single crystal X-ray structure. All the synthesized compounds were screened for their anti-inflammatory activities by carrageenan induced paw edema method. Anti-inflammatory screening indicated that, compounds 4d, 4e, and 4h were found to be biologically active whereas remaining compounds showed poor antiinflammatory activity. Also molecular docking studies were also performed for compounds which showed good antiinflammatory activity. © Springer Science+Business Media, LLC 2011.
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    Bio-conjugation of Bacillus Fastidiosus-Uricase with methoxy polyethylene glycol derivative and study of physiochemical properties
    (2012) Nanda, P.; JagadeeshBabu, P.E.; Tekalkote, S.; Kunnummal, B.M.; Kaleekkal, N.
    Uricase (EC 1.7.3.3, UC) is an enzyme belonging to the class of oxidoreductases and catalyses the oxidation of uric acid to allantoin, carbon dioxide and hydrogen peroxide. In this present work, Uricase from Bacillus fastidisous was conjugated with methoxypolyethyleneglycol p-nitrophenyl carbonate (mPEG-np) a polyethylene glycol derivative, in order to improve the pharmaceutical properties of therapeutic enzyme uricase. The PEGylated conjugates (uricase-mPEG-np) were synthesized using various ratios of uricase and mPEG-np to get maximum residual activity. The PEGylated uricase showed maximum residual uricolytic activity of 90.9% compared to the unmodified uricase, which was achieved at a ratio of 1:17 of uricase to mPEG-np. PEGylated uricase was further characterized using SDS-PAGE to determine its final molecular weight and approximate number of mPEG molecules attached. The result showed that the molecular weight was increased to 79.4 KDa and the number of mPEG molecules bound per subunit of uricase was approximately 9. Stability of the PEGylated uricase at various temperature and pH was studied and found to be 32°C and pH of 9.0. Further the mechanism of binding and possible sites of binding were studied using molecular modeling and docking software tool ArgusLab 4.0.1 and the two-dimensional image of docked uricase were generated.
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    New dihydropyridine derivatives: Anti-inflammatory, analgesic and docking studies
    (2013) Ulloora, S.; Kumar, S.; Shabaraya, R.; Vasudeva Adhikari, A.V.
    The present article describes synthesis of new diethyl 2,6-dimethyl-4-(4- (2-substituted amino-2-oxoethoxy) phenyl)-1,4-dihydropyridine-3,5-dicarboxylates (6a-10b) following multistep synthetic route. Structures of newly synthesized intermediates and title compounds were established by spectral and elemental analyses. The final compounds were screened for their in vivo anti-inflammatory and analgesic activities by carrageenan-induced paw oedema and tail immersion methods, respectively. Moreover, molecular docking studies were carried out for active compounds 6c, 6d, 7d, 8 and 10b to study their mode of action, meanwhile in vivo results indicated that these compounds displayed rapid onset of anti-inflammatory action and exhibited prominent activity when compared with the standard drug. Compounds 6d and 7d carrying amide functionality showed the highest anti-inflammatory as well as analgesic activities. The molecular docking results emphasised the in vivo data and all docked molecules were found to display very low binding constant values in nanomolar scale. © 2012 Springer Science+Business Media, LLC.
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    Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition
    (2013) Panathur, N.; Udayakumar, U.; Koushik, P.V.; Alvala, M.; Yogeeswari, P.; Sriram, D.; Kumar, V.
    In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-[4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3- yl]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia. © 2013 Elsevier Masson SAS. All rights reserved.
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    New indole-isoxazolone derivatives: Synthesis, characterisation and in vitro SIRT1 inhibition studies
    (Elsevier Ltd, 2015) Panathur, N.; Gokhale, N.; Udayakumar, U.; Koushik, P.V.; Yogeeswari, P.; Sriram, D.
    A new series of indole-isoxazolone hybrids bearing substituted amide, substituted [(1,2,3-triazol-4-yl)methoxy]methyl group or substituted benzylic ether at position-2 of the indole nucleus was synthesised using a facile synthetic route and the molecules were characterised using spectroscopic techniques. The molecules were screened against three human cancer cell lines to evaluate their in vitro cytotoxic property. Most of the trifluoromethyl substituted derivatives exhibited better growth inhibition activity than their methyl substituted analogues. The SIRT1 inhibition activity of two potent molecules (I17 and I18) was investigated and the SIRT1 IC50 values are 35.25 and 37.36 ?M, respectively for I17 and I18. The molecular docking studies with SIRT1 enzyme revealed favourable interactions of the molecule I17 with the amino acids constituting the receptor enzyme. © 2015 Elsevier Ltd. All rights reserved.
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    New INH-pyrazole analogs: Design, synthesis and evaluation of antitubercular and antibacterial activity
    (Elsevier Ltd, 2015) Nayak, N.; Ramprasad, J.; Udayakumar, U.
    With the aim of developing promising antitubercular and antibacterial leads, we have designed and synthesized a new series of isonicotinohydrazide based pyrazole derivatives (5a-r). All new derivatives (4a-b and 5a-r) were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) strain. Four compounds 5j, 5k, 5l and 4b emerged as promising antitubercular agents with MIC of ?4.9 ?M which is much lower than the MIC of the first line antitubercular drug, ethambutol. The 3-chlorophenyl substituent at position-3 of the pyrazole ring enhanced the antiTB activity of the molecules. Three derivatives 5b, 5k and 4b exhibited promising antibacterial activity against the tested bacterial strains. The active molecules were nontoxic to normal Vero cells and showed high selectivity index (>160). The structure and antitubercular activity relationship was further supported by in silico molecular docking study of the active compounds against enoyl acyl carrier protein reductase (InhA) enzyme of M. tuberculosis. © 2015 Published by Elsevier Ltd.
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    Design of new phenothiazine-thiadiazole hybrids via molecular hybridization approach for the development of potent antitubercular agents
    (Elsevier Masson SAS 62 rue Camille Desmoulins Issy les Moulineaux Cedex 92442, 2015) Ramprasad, J.; Nayak, N.; Udayakumar, U.
    A new library of phenothiazine and 1,3,4-thiadiazole hybrid derivatives (5a-u) was designed based on the molecular hybridization approach and the molecules were synthesized in excellent yields using a facile single-step chloro-amine coupling reaction between 2-chloro-1-(10H-phenothiazin-10-yl)ethanones and 2-amino-5-subsituted-1,3,4-thiadiazoles. The compounds were evaluated for their in vitro inhibition activity against Mycobacterium tuberculosis H37Rv (MTB). Compounds 5g and 5n were emerged as the most active compounds of the series with MIC of 0.8 ?g/mL (?1.9 ?M). Also, compounds 5a, 5b, 5c, 5e, 5l and 5m (MIC = 1.6 ?g/mL), and compounds 5j, 5k and 5o (MIC = 3.125 ?g/mL) showed significant inhibition activity. The structure-activity relationship demonstrated that an alkyl (methyl/npropyl) or substituted (4-methyl/4-Cl/4-F) phenyl groups on the 1,3,4-thiadiazole ring enhance the inhibition activity of the compounds. The cytotoxicity study revealed that none of the active molecules are toxic to a normal Vero cell line thus proving the lack of general cellular toxicity. Further, the active molecules were subjected to molecular docking studies with target enzymes InhA and CYP121. © 2015 Elsevier Masson SAS. All rights reserved.
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    Ionic liquid-promoted one-pot synthesis of thiazole-imidazo[2,1-b][1,3,4]thiadiazole hybrids and their antitubercular activity
    (Royal Society of Chemistry, 2016) Ramprasad, J.; Nayak, N.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.
    In this paper, we report the facile and efficient one-pot three-component synthesis of 1-((6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)-2-(4-phenylthiazol-2-yl)hydrazine derivatives (5a-w) using an ionic liquid, namely 1-butyl-3-methylimidazolium bromide ([Bmim]Br). The compounds were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis. Compound 5s showed the highest inhibitory activity with an MIC of 6.03 ?M which is slightly lower than the MIC values of standard drugs ethambutol (15.3 ?M) and ciprofloxacin (9.4 ?M). Four other compounds of the series viz.5e, 5i, 5t and 5w also showed significant inhibitory activity with MIC values in the range of 11.7-13.9 ?M. The structure-activity relationship revealed that the trifluoromethyl substitution at position-2 and p-chlorophenyl substitution at position-6 of the imidazo[2,1-b][1,3,4]thiadiazole ring enhanced the inhibitory activity. Also, the methyl, methoxy, fluoro or nitro substituents on the thiazole ring enhanced the activity of the compounds. None of the active compounds were toxic to a normal cell line (NIH 3T3), which signifies the lack of general cellular toxicity of the molecules. In silico molecular docking studies revealed the favourable interaction of the potent compounds with the target enzymes InhA and CYP121. © The Royal Society of Chemistry 2016.
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    Design and: In vitro biological evaluation of substituted chalcones synthesized from nitrogen mustards as potent microtubule targeted anticancer agents
    (Royal Society of Chemistry, 2017) Sabina, X.J.; Karthikeyan, J.; Velmurugan, G.; Muthu Tamizh, M.M.; Nityananda Shetty, A.N.
    A new series of p-[N,N-bis(2-chloroethyl)amino]benzaldehyde substituted chalcone derivatives were designed and synthesized, and their structures were characterized by spectroscopic techniques and single crystal XRD studies. Compounds 3a-f crystallized in the triclinic system with a centrosymmetric space group P1, except for crystal 3c which crystallized in the monoclinic crystal system with a centrosymmetric space group P21/c. Molecular docking studies were utilized to reveal the binding mode of the derivatives to identify new tubulin inhibitors. Density functional theory calculations were performed to understand the structural and electronic properties of these chalcones. The DFT results show that the HOMOs of all the chalcones lie in the range of -5.65 to -6.17 eV and the LUMOs in the range of -2.01 to -3.21 eV. The experimental results are well supported by the theoretical structural analysis. The biological activity of these compounds showed high potency of growth inhibitory effects with sub-micromolar IC50 values ranging from 0.089 to 0.200 ?M against A549 and HepG2 cancer cell lines. Furthermore, these compounds exhibited a strong inhibitory effect on tubulin polymerization. 3e showed the highest mean activity against both the cancer cells and in tubulin inhibition. This correlated well with the theoretical results from the pharmacophore binding model. Hence, these six compounds, particularly 3e, could be considered as potential leads in the development of new anticancer agents. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017.