in silico drug target identification

In conclusion, for each BC subtype and for all 50 bootstraps we obtained 10 × 50 couples of pathways with the best AUC values validated on the testing dataset.

The authors developed their computational algorithm (PCI index) considering all those KEGG pathways that contain any of the primary targets of the Food and Drug Administration (FDA) approved drugs in BC.

51 pathogen-specific drug targets was labor intensive, involving comparison of candidate pathogen 52 targets against all known eukaryotic sequences to filter out targets likely to occur in the human [9]. Binding residues present in largest pocket of modelled protein is presented in orange color. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. 2015;16:171. https://doi.org/10.1186/s13059-015-0732-z. Fiocruz LV3954, L. sp. In silico identification of drug target pathways in breast cancer subtypes using pathway cross-talk inhibition. Bian et al., 2011 discovered that to regulate the ABC transporters, riboswitches restricted to interact first with thiamine pyrophosphates due to which pathogen failed to grow in insufficient environment of thiamine pyrophosphate [52]. Article 

Once a map of pathway cross-talk specific of a disease is known, a potential solution hindering the formation of alternative signaling pathways created in response to therapy could be the administration of drugs able to act on both direct and indirect targets (generated by the inhibition of direct targets). 2005 [20,51].

Graudenzi A, Cava C, Bertoli G, Fromm B, Flatmark K, Mauri G, Castiglioni I. Pathway-based classification of breast cancer subtypes. Every time we obtained the top-10 pairs of subtype cross-talking pathways with the best AUC value. <>stream To classify luminal A, we considered the expression levels of 2693 genes from the independent GEO dataset GSE58212 and belonging to our luminal A pathway network. [143 0 R] 2014;33(9):1073–81. 134 0 obj Günther S, Kuhn M, Dunkel M, Campillos M, Senger C, Petsalaki E, Ahmed J, Urdiales EG, Gewiess A, Jensen LJ, Schneider R, Skoblo R, Russell RB, Bourne PE, Bork P, Preissner R. SuperTarget and Matador: resources for exploring drug-target relationships. Introduction: Compounds containing thiadiazole moiety are cognized to possess with variety of clinical and therapeutic activity. Huang P, Chandra V, Rastinejad F. Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics.

Benjamini Y, Hochberg Y. However, we optimized our computational method based on the reported databases by reducing the bias on data from such databases performing a Monte Carlo cross-validation. 2000;5(3):271–81. %PDF-1.4 %����

Gujarat reported 130 deaths in 2011 within a span of two months due to leptospirosis. 4c).

From a BC data set of The Cancer Genome Atlas, we have identified different networks of cross-talking pathways for different BC subtypes, validated using an independent BC dataset from Gene Expression Omnibus.

For each combination of pathways we estimated the Area Under Curve (AUC) values by cross-validation method (k-fold cross-validation, k = 10).

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Google Scholar. Table 5 shows de-regulated pathways in common in all subtypes, which can be considered as responsible for the initial stages of BC, and those de-regulated pathways present only in one subtype, specific of the behaviour of that subtype. The inhibition of 2271/4950 combinations of pathways reduces the NE of the pathway network with values that ranges from 0.3189 to 0.3492 (Fig.

Combination therapy increases the efficacy of docetaxel, vinblastine and tamoxifen in cancer cells. The ‘Epithelial Adherens Junction Signaling Pathway’, if inhibited, reduces the NE of 2.3% and it is target of docetaxel. Controlling the false discovery rate: a practical and powerful approach to multiple testing. LT2116 proteome consists of most elevated number of proteins while L. borgpetersenii serovar Hardjo-bovis str. Among drug target pathways found in our DTPN we found 1 pathway of the top 5 pathways playing the major role in the reduction of NE ... Our in silico method is based on the identification and quantification of the pathway cross-talk for distinct cancer subtypes.

We quantified this effect by PCI. PPP1R10 belongs to ‘Protein Kinase A Signaling’. Network of L. borgpetersenii comprised of 38 nodes with 41 edges. 26702580; E-mail: Aeromonas hydrophila is a major pathogen both of aquatic and 6b). Writing – review & editing, * E-mail: [email protected] (CSR); [email protected] (DP), Affiliation Pathway cross-talk can be an ideal framework to assess pathway interactions that could originate phenomena of resistance or inefficacy of the drug. Samadi N, Ghanbari P, Mohseni M, Tabasinezhad M, Sharifi S, Nazemieh H, Rashidi MR. [6], our application presents several differences: (1) the Jaeger’s work was focused on cross-talk due to the presence of overlapping genes between different pathways, we instead explore cross-talk as regulatory interactions among distinct pathways; (2) in Jaeger’s work all KEGG pathways were considered, we instead made a selection on pathways based on their different activity in different cancer subtype vs normal tissues.

DTPN of luminal B was built considering the 27 pathways that inhibited reduced the NE.

Gene lpxD-2, kdsB-2 and lpxK demonstrated the most noteworthy degree followed by kdtA, lpxD-1, lpxB and lpxC with degree 6 (Table 4; Fig 5A). Structurally conserved elements were identified and formatted with ESPript 3.0 to obtain the conserved and semi conserved residues of both the chokepoints [35]. CAS  Yes Clifton, VA 20124 BIC/NTF/1/2013-2014 dated 18/02/2013. Thus, the inhibition of couples of pathways of the cloud seems to reduce the efficiency more than individual pathway. The current study is an adoption of advanced subtractive and comparative genomic approach and further augmented to protein-protein interaction network and metabolomics analysis.

Among the hub proteins, 16 are also shortlisted from the set of 34 common putative drug targets.

This pathway is involved in basal DTPN since its inhibition can reduce the NE of 4% (PCI). In silico and in vitro target identification research to cure leptospirosis, till date, have been more focused towards most pathogenic L. interrogans serovars named Lai and Copenhagani [20,46–47].

Among these common drug targets three are non enzyme and 31 are enzymes (Table 2). A new-NE (nNE) is calculated. As effect of this operation, nNE was < NE or > NE, resulting in increasing or decreasing the drug efficiency, respectively.

Fiocruz L1-130 and L. borgpetersenii serovar Hardjo-bovis str. As with other infectious diseases, report of antimicrobial resistance to existing therapeutic arsenal poses challenges in the management of disease.

L550 and L. interrogans serovar Copenhageni str.

Fiocruz LV4135, L. sp.

Therefore, understanding how and where the pathway cross-talk can be inhibited by drug treatments during a disease process ideally could lead to more effective therapies, reducing the problem of drug resistance.

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����_ŕ�������_,��\��k����_��)��� ��S���ڢb�$�4`�]�5�_0��s%k�R��\�Ϯ��6#�"(����O�6Y ��{���V�[�ݭ=�:C?�H*�&n�����D��Ovh"��@ ���u���-&�� �p��lx�aԗ�l�v��I��������"V8��t�6��L6��N���>U!H,S$�&:#=�ҭ�r�E���K�2�M�6-��p��ޑ����"٩�����A-X+�!��eN�F��[email protected]¢-���I�u � 2012;149(2):307–21. Authors: Sharma, Vibhuti | Gupta, Preeti | Dixit, Aparna, Affiliations: Gene Regulation Laboratory, School of Biotechnology, We compared the decrease of pathway cross-talk within the DTCN followed by inhibition of drug target pathways. Cell.

In basal subtype we found that the inhibition of EIF2 Signaling reduces the efficiency of 8.5%.

We validated our network-based models of BC subtype pathways and BC drug target pathways.

Additional file 2 shows nNE values in the luminal B after the inhibition of individual and combined pathway(s).

This could be helpful to cure the leptospiral infections successfully. In addition, genome scale metabolic network reconstruction and choke point analysis revealed cobA (porphyrin and chlorophyll metabolism) and thiL (thiamine metabolism) as chokepoints in their respective metabolic pathways.

Google Scholar. Biomedical Informatics Centre, National Institute of Pathology-Indian Council of Medical Research, New Delhi, India, Roles Red lines represent the efficiency of the original network (NE).

Pathway network), and we simulated in silico the drug-induced inhibition of pathways (6. <> Bernards R. A missing link in genotype-directed cancer therapy. Copyright ©2020 IOS Press All rights reserved. ACTG2 belongs to ‘Tight Junction Signaling’ pathway.

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