Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Pharmocogenomics is a Multidirectional Street

 

Author and Curator: Demet Sag, PhD

There was a big undertake between CTD-Pfizer collaboration for manual curation of scientific articles text mined for drug-disease has a great partnering between public and private entities.  This effort leads common needs of the environmental health science and pharmaceutical communities. This drug and phenotype interactions as a result of  a collection of 88,629 articles relating over 1,200 pharmaceutical drugs to their potential toxicities in cardiovascular, neurological, kidney and liver .

In one year, CTD biocurators curated 254,173 toxicogenomic interactions

152,173 chemical-disease,

58,572 chemical-gene,

5,345 gene-disease and

38,083 phenotype interactions

Furthermore, drugability and genomics depends on bioinformatics for finding drug targets. In this token the Drug-Gene Interaction database (DGIdb) can be reached at http://dgidb.org/.

This database has an advantage since helps to prioritize drug development based on mutation types and potential druggable genes from existing resources.

Another method is pathway screening to identify the druggable genes that leads to development of an organism or cell or divergence during evolution.

However,  this process is not a straight line there are other factors that needs to be applied for a proper target identification. There are warning signs and cautions needs to be taken.

Identification of these side effects in addition to toxicities is important for the proper development. This is like yin and yen since one side trying to make it correct and the other side is destroying yet the positive affects wins the case.

Anticoagulant therapy has many adverse effects yet the patients prescribed since there is a need to correct the case yet there are expected adverse reactions.

As a  result, predicting the side effects and benchmarking them to understand the real problems in vivo is necessary.

Yet, still there is one more step to combine off target and side effects before making a decision based on the original drug- gene targets.  The applications opens doors from cell modifications specially in stem cells, vaccines, sensors, bioinformatics and wireless technologies as examples of the few.

There are other applications of knowing the gene-drug relations such as development of biosensors, sensors, vaccines, immune responses and redesigning or remodulating  the cells. In 1995  the complete genome of a pathogenic bacterium published . Since then virologist immunologists, vaccineoloist are all lookin for epitope mapping tools to screen vaccine candidates.  This new wave is called  ‘genome to vaccine’.

The examples of bionformatics tools currently, in use are for example, include to search for unique or multi-HLA-restricted T cell epitopes (piMatrix),  to find epitopes that are conserved across variant strains of the same pathogen (Conservatrix), to identify similarity to ‘self’ (BlastiMer) or  to assemble putative epitopes into strings if they overlap (EpiAssembler).

As a result, several solutions are developed to identify novel targets by complementing or combining methods, or following up the clinical trials, subtractive genome analysis are the name of few. In addtion, the combinatorial algorithm for maximizing inclusion drugs but minimize off-targets is necessary.

 

REFERENCES

http://ctdbase.org/

Targeted journal curation as a method to improve data currency at the Comparative Toxicogenomics Database.

Davis AP¹, Johnson RJ, Lennon-Hopkins K, Sciaky D, Rosenstein MC, Wiegers TC, Mattingly CJ.

Database (Oxford). 2012 Dec 6;2012:bas051. doi: 10.1093/database/bas051. Print 2012.

DGIdb: mining the druggable genome.

Nat Methods. 2013 Dec;10(12):1209-10. doi: 10.1038/nmeth.2689. Epub 2013 Oct 13.

Griffith M¹, Griffith OL, Coffman AC, Weible JV, McMichael JF, Spies NC, Koval J, Das I, Callaway MB, Eldred JM, Miller CA, Subramanian J, Govindan R, Kumar RD, Bose R, Ding L, Walker JR, Larson DE, Dooling DJ, Smith SM, Ley TJ, Mardis ER, Wilson RK.

A CTD-Pfizer collaboration: manual curation of 88,000 scientific articles text mined for drug-disease and drug-phenotype interactions.

Davis AP¹, Wiegers TC, Roberts PM, King BL, Lay JM, Lennon-Hopkins K, Sciaky D, Johnson R, Keating H, Greene N, Hernandez R, McConnell KJ,Enayetallah AE, Mattingly CJ.

Database (Oxford). 2013 Nov 28;2013:bat080. doi: 10.1093/database/bat080. Print 2013.

Text mining effectively scores and ranks the literature for improving chemical-gene-disease curation at the comparative toxicogenomics database.

Davis AP¹, Wiegers TC, Johnson RJ, Lay JM, Lennon-Hopkins K, Saraceni-Richards C, Sciaky D, Murphy CG, Mattingly CJ.

PLoS One. 2013 Apr 17;8(4):e58201. doi: 10.1371/journal.pone.0058201. Print 2013.

Systematic identification of proteins that elicit drug side effects.

Kuhn M¹, Al Banchaabouchi M, Campillos M, Jensen LJ, Gross C, Gavin AC, Bork P.

Mol Syst Biol. 2013;9:663. doi: 10.1038/msb.2013.10.

Prediction of immunogenicity for therapeutic proteins: state of the art.

De Groot AS¹,

Moise L. Curr Opin Drug Discov Devel. 2007 May;10(3):332-40.

De-immunization of therapeutic proteins by T-cell epitope modification.

De Groot AS¹, Knopp PM, Martin W.

Dev Biol (Basel). 2005;122:171-94.

From immunome to vaccine: epitope mapping and vaccine design tools.

De Groot AS¹, Martin W.

Novartis Found Symp. 2003;254:57-72; discussion 72-6, 98-101, 250-2.

Combinatorial therapy discovery using mixed integer linear programming.

Pang K¹, Wan YW, Choi WT, Donehower LA, Sun J, Pant D, Liu Z.

1.  2014 Feb 21. [Epub ahead of print]

Other articles on Pharmacogenomics published in this Open Access Online Scientific Journal include the following:

Pharmacogenomics for Cardiovascular Diseases

Blood Pressure Response to Antihypertensives: Hypertension Susceptibility Loci Study

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/02/blood-pressure-response-to-antihypertensives-atenolol-and-hydrochlorothiazide-hypertension-susceptibility-loci-study/ 

Statin-Induced Low-Density Lipoprotein Cholesterol Reduction: Genetic Determinants in the Response to Rosuvastatin

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/02/statin-induced-low-density-lipoprotein-cholesterol-reduction-genetic-determinants-in-the-response-to-rosuvastatin/

SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/02/snps-in-apoe-are-found-to-influence-statin-response-significantly-less-frequent-variants-in-pcsk9-and-smaller-effect-sizes-in-snps-in-hmgcr/

Voltage-Gated Calcium Channel and Pharmacogenetic Association with Adverse Cardiovascular Outcomes: Hypertension Treatment with Verapamil SR (CCB) vs Atenolol (BB) or Trandolapril (ACE)

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/02/voltage-gated-calcium-channel-and-pharmacogenetic-association-with-adverse-cardiovascular-outcomes-hypertension-treatment-with-verapamil-sr-ccb-vs-atenolol-bb-or-trandolapril-ace/

Response to Rosuvastatin in Patients With Acute Myocardial Infarction: Hepatic Metabolism and Transporter Gene Variants Effect

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/01/02/response-to-rosuvastatin-in-patients-with-acute-myocardial-infarction-hepatic-metabolism-and-transporter-gene-variants-effect/

Helping Physicians identify Gene-Drug Interactions for Treatment Decisions: New ‘CLIPMERGE’ program – Personalized Medicine @ The Mount Sinai Medical Center

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/04/15/helping-physicians-identify-gene-drug-interactions-for-treatment-decisions-new-clipmerge-program-personalized-medicine-the-mount-sinai-medical-center/

Leveraging Mathematical Models to Understand Population Variability in Response to Cardiac Drugs: Eric Sobie, PhD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/04/22/leveraging-mathematical-mod

els-to-understand-population-variability-in-response-to-cardiac-drugs-eric-s

obie-phd/ 

Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/02/04/is-pharmacogenetic-based-dosing-of-warfarin-superior-for-anticoagulation-control/