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2D-QSAR, Docking Studies, and In Silico ADMET Prediction of Polyphenolic Acetates as Substrates for Protein Acetyltransferase Function of Glutamine Synthetase of Mycobacterium tuberculosis  [PDF]
Prija Ponnan,Shikhar Gupta,Madhu Chopra,Rashmi Tandon,Anil S. Baghel,Garima Gupta,Ashok K. Prasad,Ramesh C. Rastogi,Mridula Bose,Hanumantharao G. Raj
ISRN Structural Biology , 2013, DOI: 10.1155/2013/373516
Abstract: A novel transacetylase (TAase) function of glutamine synthetase (GS) in bacterial species such as Mycobacterium smegmatis and Mycobacterium tuberculosis H37Rv was established by us, termed as mycobacterial TAase (MTAase). Several polyphenolic acetates (PAs) were found to be substrates for MTAase by inhibiting certain receptor proteins such as glutathione S-transferase by way of acetylation. The present work describes the descriptor-based 2D-QSAR studies developed for a series of PA synthesized by us and evaluated for MTAase and antimycobacterial activity using stepwise multiple linear regression method with the kinetic constants and the minimum inhibitory constant (MIC) as the dependent variables, to address the fact that TAase activity was leading to the antimycobacterial activity. Further, blind docking methods using AutoDock were carried out to study the interaction of potent PA with the crystal structure of M. tuberculosis GS. PAs were predicted to bind M. tuberculosis GS on the protein surface away from the known active site of GS. Subsequent focussed/refined docking of potent PA with GS showed that the -amino group of Lys4 of GS formed a cation- interaction with the benzene ring of PA. Also, ADMET-related descriptors were calculated to predict the pharmacokinetic properties for the selection of the effective and bioavailable compounds. 1. Introduction Our laboratory is credited for the discovery of novel TAase which catalyzes the possible transfer of acetyl group from PA to certain functional proteins such as GST, cytochrome P-450 reductase, and nitric oxide synthase (NOS) leading to their functional modifications [1–3]. An assay procedure was developed utilizing the inhibition of cytosolic GST brought about by TAase-catalyzed acetylation by PA. Both the substrates, namely, the target protein GST and the acetyl group donor PAs were found to take part in the TAase-catalyzed bimolecular reaction [2]. This assay procedure was utilized to purify TAase from tissues like human placenta and rat liver and characterized as calreticulin, a calcium-binding ER luminal protein [4, 5]. The acetylation of receptor proteins such as GST and NOS at ε-amino group lysine residues was established by immunoblotting using acetylated lysine antibody and mass spectrometry [6, 7]. Recently, TAase was identified and established by us in bacterial species such as Mycobacterium smegmatis [8] and Mycobacterium tuberculosis (Mtb) H37Rv [9] as glutamine synthetase (GS). Glutamine synthetase catalyzes the conversion of glutamate to glutamine in the presence of ammonium ion with
2D QSAR studies on a series of bifonazole derivatives with antifungal activity
Mota, Sabrina G. R.;Barros, Tania F.;Castilho, Marcelo S.;
Journal of the Brazilian Chemical Society , 2009, DOI: 10.1590/S0103-50532009000300007
Abstract: candida albicans (ca) has been identified as the major opportunistic pathogen in immunosuppressed patients. most of currently available drugs are either highly toxic or becoming ineffective against resistant strains. an approach to overcome this burden relies on azole derivatives with increased potency and selectivity. aiming at shedding some light on structural and chemical features that are important for the antifungal activity of azole derivatives, classical 2d qsar and hologram qsar (hqsar) studies were performed for a diverse set of 52 bifonazole derivatives with antifungal activity. topological descriptors, employed in classical qsar studies, resulted in models with low correlation (r2 = 0.38, q2 = 0.27) and lack of predictive power (r2pred = -0.6). on the other hand molecular holograms afforded hqsar models with good correlation coefficients (r2 = 0.92, q2 = 0.65) and good predictive ability (r2pred = 0.79).
Sulfonamide Based β-Carbonic Anhydrase Inhibitors: 2D QSAR Study  [PDF]
Meenakshi N. Deodhar,Priyanka L. Khopade,Mahesh G. Varat
ISRN Medicinal Chemistry , 2013, DOI: 10.1155/2013/107840
Abstract: The carbonic anhydrases (CAs) (or carbonate dehydratases) form a family of metalloenzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons (or vice versa), a reversible reaction that occurs rather slowly in the absence of a catalyst. The β-CAs have been characterized in a high number of human pathogens, such as the fungi/yeasts Candida albicans, Candida glabrata, Cryptococcus neoformans, and Saccharomyces cerevisiae and the bacteria Helicobacter pylori, Mycobacterium tuberculosis, Haemophilus influenzae, Brucella suis, and Streptococcus pneumonia. The β-CAs in microorganisms provide physiological concentration of carbon dioxide and bicarbonate (CO2/ ) for their growth. Inhibition of β-CAs from the pathogenic microorganism is recently being explored as a novel pharmacological target to treat infections caused by the these organisms. The present study aimed to establish a relationship between the β-CAs inhibitory activity for structurally related sulphonamide derivatives and the physicochemical descriptors in quantitative terms. The statistically validated two-dimensional quantitative structure activity relationship (2D QSAR) model was obtained through multiple linear regression (MLR) analysis method using Vlife molecular design suits (MDS). Five descriptors showing positive and negative correlation with the β-CAs inhibitory activity have been included in the model. This validated 2D QSAR model may be used to design sulfonamide derivatives with better inhibitory properties. 1. Introduction The CAs belong to the family of metalloenzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons (or vice versa), a reversible reaction that occurs rather slowly in the absence of a catalyst. The active site of most carbonic anhydrases contains a zinc ion [1]. Genetically five different types of CAs enzymes are known till date. The α-CAs are present in vertebrates, protozoa, algae, and some bacteria and also in cytoplasm of green plants [2]. While the β-CAs are predominantly found in bacteria, algae, chloroplasts of both mono- and dicotyledons and some fungi and archaea [3], the γ-CAs are found in archaea and some bacteria [4]. Both the δ-and ζ-CAs forms are present only in marine diatoms [5]. These enzymes which catalyze the interconversion between carbon dioxide and bicarbonate, with release of a proton, are involved not only in pH homeostasis and regulation but also in biosynthetic reactions, such as gluconeogenesis and ureagenesis in animals, CO2 fixation (in plants and
Comparative QSAR analysis of cyclo-oxygenase2 inhibiting drugs
Arumugam Mohanapriya,Dayalan Achuthan
Bioinformation , 2012,
Abstract: Cyclo-oxygenase 2 (COX2) inhibiting drugs were subjected to comparative quantitative structure activity relationship (QSAR) analysis with an attempt to derive and to understand the relationship between the biological activity and molecular descriptors by multiple regression analysis. The different drugs that inhibit cyclo-oxygenase 2 enzyme were compared instead of subjecting one drug and its derivatives to QSAR analysis. The study was conducted to look for the common structural features between the drugs which confer to a good biological activity. Based on the regression analysis the following descriptors were finalized as the components fitting best in the regression equations: Ss, SCBO, RBN, nN, SIC0, IC1, and H-055. These descriptors belong to constitution (Ss, SCBO, RBN, nN), information indices (SIC0, IC1) and atom centered fragments (H-055) category. Based on these descriptors QSAR models were generated and evaluated for best structure-activity correlation. The model generated from constitution and information indices descriptors corresponds to the essential structural features of the drugs and are found to have significant correlation with COX2 inhibiting activity. This study shall help in rational drug design and synthesis of new selective cyclo-oxygenase 2 inhibitors with predetermined affinity and activity.
3D-QSAR studies on fluroquinolones derivatives as inhibitors for tuberculosis
Atanu Bhattacharjee,Baphilinia Jones Mylliemngap,Devadasan Velmurugan
Bioinformation , 2012,
Abstract: A quantitative structure activity relationship (QSAR) study was performed on the fluroquinolones known to have anti-tuberculosis activity. The 3D-QSAR models were generated using stepwise variable selection of the four methods - multiple regression (MR), partial least square regression (PLSR), principal component regression (PCR) and artificial neural networks (kNN-MFA). The statistical result showed a significant correlation coefficient q2 (90%) for MR model and an external test set of (pred_r2) -1.7535, though the external predictivity showed to improve using kNN-MFA method with pred_r2 of -0.4644. Contour maps showed that steric effects dominantly determine the binding affinities. The QSAR models may lead to a better understanding of the structural requirements of anti-tuberculosis compounds and also help in the design of novel molecules.
Exploring prospects of novel drugs for tuberculosis  [cached]
Janssen S,Jayachandran R,Khathi L,Zinsstag J
Drug Design, Development and Therapy , 2012,
Abstract: Saskia Janssen,1,2 Rajesh Jayachandran,3 Lulama Khathi,4 Jakob Zinsstag,5 Martin P Grobusch,1,2,6 Jean Pieters31Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands; 2Institute of Tropical Medicine, University of Tübingen, Germany; 3Biozentrum, University of Basel, Basel, Switzerland; 4National Reference Laboratory for Tuberculosis, National Health Laboratory Services, Johannesburg, South Africa; 5Swiss Tropical and Public Health Institute, Associated Institute to the University of Basel, Basel, Switzerland; 6Department of Infectious Diseases, Division of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaAbstract: Tuberculosis remains a disease with an enormous impact on public health worldwide. With the continuously increasing epidemic of drug-resistant tuberculosis, new drugs are desperately needed. However, even for the treatment of drug-sensitive tuberculosis, new drugs are required to shorten the treatment duration and thereby prevent development of drug resistance. Within the past ten years, major advances in tuberculosis drug research have been made, leading to a considerable number of antimycobacterial compounds which are now in the pipeline. Here we discuss a number of these novel promising tuberculosis drugs, as well as the discovery of two new potential drug targets for the development of novel effective drugs to curb the tuberculosis pandemic, ie, the coronin 1 and protein kinase G pathways. Protein kinase G is secreted by mycobacteria and is responsible for blocking lysosomal delivery within the macrophage. Coronin 1 is responsible for activating the phosphatase, calcineurin, and thereby preventing phagosome-lysosome fusion within the macrophage. Blocking these two pathways may lead to rapid killing of mycobacteria.Keywords: tuberculosis, treatment, drug-resistance, drug targets
Exploring prospects of novel drugs for tuberculosis
Janssen S, Jayachandran R, Khathi L, Zinsstag J, Grobusch MP, Pieters J
Drug Design, Development and Therapy , 2012, DOI: http://dx.doi.org/10.2147/DDDT.S34006
Abstract: ring prospects of novel drugs for tuberculosis Review (2947) Total Article Views Authors: Janssen S, Jayachandran R, Khathi L, Zinsstag J, Grobusch MP, Pieters J Published Date September 2012 Volume 2012:6 Pages 217 - 224 DOI: http://dx.doi.org/10.2147/DDDT.S34006 Received: 18 May 2012 Accepted: 28 June 2012 Published: 07 September 2012 Saskia Janssen,1,2 Rajesh Jayachandran,3 Lulama Khathi,4 Jakob Zinsstag,5 Martin P Grobusch,1,2,6 Jean Pieters3 1Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands; 2Institute of Tropical Medicine, University of Tübingen, Germany; 3Biozentrum, University of Basel, Basel, Switzerland; 4National Reference Laboratory for Tuberculosis, National Health Laboratory Services, Johannesburg, South Africa; 5Swiss Tropical and Public Health Institute, Associated Institute to the University of Basel, Basel, Switzerland; 6Department of Infectious Diseases, Division of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Abstract: Tuberculosis remains a disease with an enormous impact on public health worldwide. With the continuously increasing epidemic of drug-resistant tuberculosis, new drugs are desperately needed. However, even for the treatment of drug-sensitive tuberculosis, new drugs are required to shorten the treatment duration and thereby prevent development of drug resistance. Within the past ten years, major advances in tuberculosis drug research have been made, leading to a considerable number of antimycobacterial compounds which are now in the pipeline. Here we discuss a number of these novel promising tuberculosis drugs, as well as the discovery of two new potential drug targets for the development of novel effective drugs to curb the tuberculosis pandemic, ie, the coronin 1 and protein kinase G pathways. Protein kinase G is secreted by mycobacteria and is responsible for blocking lysosomal delivery within the macrophage. Coronin 1 is responsible for activating the phosphatase, calcineurin, and thereby preventing phagosome-lysosome fusion within the macrophage. Blocking these two pathways may lead to rapid killing of mycobacteria.
On the information content of 2D and 3D descriptors for QSAR
Oprea, Tudor I.;
Journal of the Brazilian Chemical Society , 2002, DOI: 10.1590/S0103-50532002000600013
Abstract: to gain better understanding on the information content of two-dimensional (2d) vs. three-dimensional (3d) descriptor systems, we analyzed principal component analysis scores derived from 87 2d descriptors and 798 3d (almond) variables on a set of 5998 compounds of medicinal chemistry interest. the information overlap between almond and 2d-based descriptors, as modeled by the fraction of explained variance (r2) and by seven-groups cross-validation (q2) in a two pls components model was 40%. individual component analysis indicates that the first and second principal components from the 2d-descriptors are related to the first and third dimensions from the almond pca model. the first almond component is explained (61%) by size-related descriptors, whereas the third component is marginally explained (25%) by hydrophobicity-related descriptors. surprisingly, 2d-based hydrogen-bonding descriptors did not contribute significantly in this analysis. these results do not a priori justify the choice of one methodology over the other, when performing qsar studies.
On the information content of 2D and 3D descriptors for QSAR  [cached]
Oprea Tudor I.
Journal of the Brazilian Chemical Society , 2002,
Abstract: To gain better understanding on the information content of two-dimensional (2D) vs. three-dimensional (3D) descriptor systems, we analyzed principal component analysis scores derived from 87 2D descriptors and 798 3D (ALMOND) variables on a set of 5998 compounds of medicinal chemistry interest. The information overlap between ALMOND and 2D-based descriptors, as modeled by the fraction of explained variance (r2) and by seven-groups cross-validation (q2) in a two PLS components model was 40%. Individual component analysis indicates that the first and second principal components from the 2D-descriptors are related to the first and third dimensions from the ALMOND PCA model. The first ALMOND component is explained (61%) by size-related descriptors, whereas the third component is marginally explained (25%) by hydrophobicity-related descriptors. Surprisingly, 2D-based hydrogen-bonding descriptors did not contribute significantly in this analysis. These results do not a priori justify the choice of one methodology over the other, when performing QSAR studies.
Estudos de QSAR 2D baseados em descritores topológicos e fragmentos moleculares para uma série de derivados azólicos ativos contra Candida albicans
Andrade, J?nathas G.;Freitas, Humberto F.;Castilho, Marcelo S.;
Química Nova , 2012, DOI: 10.1590/S0100-40422012000300005
Abstract: azole derivatives are the main therapeutical resource against candida albicans infection in immunocompromised patients. nevertheless, the widespread use of azoles has led to reduced effectiveness and selection of resistant strains. in order to guide the development of novel antifungal drugs, 2d-qsar models based on topological descriptors or molecular fragments were developed for a dataset of 74 molecules. the optimal fragment-based model (r2 = 0.88, q2 = 0.73 and r2pred = 0.62 with 6pcs) and descriptor-based model (r2 = 0.82, q2 = 0.79 and r2pred = 0.70 with 2 pcs), when analysed synergically, suggested that the triazolone ring and lipophilic properties are both important to antifungal activity.
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