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1.  Linking off-target kinase pharmacology to the differential cellular effects observed among PARP inhibitors 
Oncotarget  2014;5(10):3023-3028.
PARP inhibitors hold promise as a novel class of targeted anticancer drugs. However, their true mechanism of action is still not well understood following recent reports that show marked differences in cellular effects. Here, we demonstrate that three PARP drug candidates, namely, rucaparib, veliparib, and olaparib, have a clearly different in vitro affinity profile across a panel of diverse kinases selected using a computational approach that relates proteins by ligand similarity. In this respect, rucaparib inhibits nine kinases with micromolar affinity, including PIM1, PIM2, PRKD2, DYRK1A, CDK1, CDK9, HIPK2, CK2, and ALK. In contrast, olaparib does not inhibit any of the sixteen kinases tested. In between, veliparib inhibits only two, namely, PIM1 and CDK9. The differential kinase pharmacology observed among PARP inhibitors provides a plausible explanation to their different cellular effects and offers unexplored opportunities for this drug class, but alerts also on the risk associated to transferring directly both preclinical and clinical outcomes from one PARP drug candidate to another.
PMCID: PMC4102788  PMID: 24632590
PARP inhibitors; off-target pharmacology; kinase profiling; drug combinations; biomarkers
2.  Identification of host interactions for phenotypic antimalarial hits 
Journal of Cheminformatics  2014;6(Suppl 1):O12.
doi:10.1186/1758-2946-6-S1-O12
PMCID: PMC3980065  PMID: 24765110
3.  Identification of host interactions for phenotypic antimalarial hits 
Journal of Cheminformatics  2014;6(Suppl 1):O12.
doi:10.1186/1758-2946-6-S1-O12
PMCID: PMC3980065  PMID: 24765110
4.  Gathering and Exploring Scientific Knowledge in Pharmacovigilance 
PLoS ONE  2013;8(12):e83016.
Pharmacovigilance plays a key role in the healthcare domain through the assessment, monitoring and discovery of interactions amongst drugs and their effects in the human organism. However, technological advances in this field have been slowing down over the last decade due to miscellaneous legal, ethical and methodological constraints. Pharmaceutical companies started to realize that collaborative and integrative approaches boost current drug research and development processes. Hence, new strategies are required to connect researchers, datasets, biomedical knowledge and analysis algorithms, allowing them to fully exploit the true value behind state-of-the-art pharmacovigilance efforts. This manuscript introduces a new platform directed towards pharmacovigilance knowledge providers. This system, based on a service-oriented architecture, adopts a plugin-based approach to solve fundamental pharmacovigilance software challenges. With the wealth of collected clinical and pharmaceutical data, it is now possible to connect knowledge providers’ analysis and exploration algorithms with real data. As a result, new strategies allow a faster identification of high-risk interactions between marketed drugs and adverse events, and enable the automated uncovering of scientific evidence behind them. With this architecture, the pharmacovigilance field has a new platform to coordinate large-scale drug evaluation efforts in a unique ecosystem, publicly available at http://bioinformatics.ua.pt/euadr/.
doi:10.1371/journal.pone.0083016
PMCID: PMC3859628  PMID: 24349421
5.  Prediction of the P. falciparum Target Space Relevant to Malaria Drug Discovery 
PLoS Computational Biology  2013;9(10):e1003257.
Malaria is still one of the most devastating infectious diseases, affecting hundreds of millions of patients worldwide. Even though there are several established drugs in clinical use for malaria treatment, there is an urgent need for new drugs acting through novel mechanisms of action due to the rapid development of resistance. Resistance emerges when the parasite manages to mutate the sequence of the drug targets to the extent that the protein can still perform its function in the parasite but can no longer be inhibited by the drug, which then becomes almost ineffective. The design of a new generation of malaria drugs targeting multiple essential proteins would make it more difficult for the parasite to develop full resistance without lethally disrupting some of its vital functions. The challenge is then to identify which set of Plasmodium falciparum proteins, among the millions of possible combinations, can be targeted at the same time by a given chemotype. To do that, we predicted first the targets of the close to 20,000 antimalarial hits identified recently in three independent phenotypic screening campaigns. All targets predicted were then projected onto the genome of P. falciparum using orthologous relationships. A total of 226 P. falciparum proteins were predicted to be hit by at least one compound, of which 39 were found to be significantly enriched by the presence and degree of affinity of phenotypically active compounds. The analysis of the chemically compatible target combinations containing at least one of those 39 targets led to the identification of a priority set of 64 multi-target profiles that can set the ground for a new generation of more robust malaria drugs.
Author Summary
There is an urgent need for new antimalarials acting through novel mechanisms of action that can overcome the increasing incidence of resistance observed for currently used drugs. In this respect, drug polypharmacology is emerging as an attractive strategy to reduce the chances of the parasite evolving drug resistance. Although there were close to 20,000 antimalarial hits recently identified from three independent phenotypic screenings, the molecular targets through which most of those active compounds exert their antimalarial action are unfortunately unknown at present. To address this issue, a computational approach was first used to predict their protein targets. Statistical analyses were applied to detect any enrichment of phenotypically active compounds in P. falciparum targets, leading to a final list of 39 putative high-priority targets for malaria drug discovery. The presence of at least one high-priority target in the target profile predicted for the antimalarial hits was then used as a constraint to identify a priority set of 64 multi-target profiles. Multi-target strategies based on such profiles can set the basis for designing a next generation of more robust malaria drugs.
doi:10.1371/journal.pcbi.1003257
PMCID: PMC3798273  PMID: 24146604
7.  Drug-Induced Acute Myocardial Infarction: Identifying ‘Prime Suspects’ from Electronic Healthcare Records-Based Surveillance System 
PLoS ONE  2013;8(8):e72148.
Background
Drug-related adverse events remain an important cause of morbidity and mortality and impose huge burden on healthcare costs. Routinely collected electronic healthcare data give a good snapshot of how drugs are being used in ‘real-world’ settings.
Objective
To describe a strategy that identifies potentially drug-induced acute myocardial infarction (AMI) from a large international healthcare data network.
Methods
Post-marketing safety surveillance was conducted in seven population-based healthcare databases in three countries (Denmark, Italy, and the Netherlands) using anonymised demographic, clinical, and prescription/dispensing data representing 21,171,291 individuals with 154,474,063 person-years of follow-up in the period 1996–2010. Primary care physicians’ medical records and administrative claims containing reimbursements for filled prescriptions, laboratory tests, and hospitalisations were evaluated using a three-tier triage system of detection, filtering, and substantiation that generated a list of drugs potentially associated with AMI. Outcome of interest was statistically significant increased risk of AMI during drug exposure that has not been previously described in current literature and is biologically plausible.
Results
Overall, 163 drugs were identified to be associated with increased risk of AMI during preliminary screening. Of these, 124 drugs were eliminated after adjustment for possible bias and confounding. With subsequent application of criteria for novelty and biological plausibility, association with AMI remained for nine drugs (‘prime suspects’): azithromycin; erythromycin; roxithromycin; metoclopramide; cisapride; domperidone; betamethasone; fluconazole; and megestrol acetate.
Limitations
Although global health status, co-morbidities, and time-invariant factors were adjusted for, residual confounding cannot be ruled out.
Conclusion
A strategy to identify potentially drug-induced AMI from electronic healthcare data has been proposed that takes into account not only statistical association, but also public health relevance, novelty, and biological plausibility. Although this strategy needs to be further evaluated using other healthcare data sources, the list of ‘prime suspects’ makes a good starting point for further clinical, laboratory, and epidemiologic investigation.
doi:10.1371/journal.pone.0072148
PMCID: PMC3756064  PMID: 24015213
8.  Cross-Pharmacology Analysis of G Protein-Coupled Receptors 
Current topics in medicinal chemistry  2011;11(15):1956-1963.
The degree of applicability of chemogenomic approaches to protein families depends on the accuracy and completeness of pharmacological data and the corresponding level of pharmacological similarity observed among their protein members. The recent public domain availability of pharmacological data for thousands of small molecules on 204 G protein-coupled receptors (GPCRs) provides a firm basis for an in-depth cross-pharmacology analysis of this superfamily. The number of protein targets included in the cross-pharmacology profile of the different GPCRs changes significantly upon varying the ligand similarity and binding affinity criteria. However, with the exception of muscarinic receptors, aminergic GPCRs distinguish themselves from the rest of the members in the family by their remarkably high levels of pharmacological similarity among them. Clusters of non-GPCR targets related by cross-pharmacology with particular GPCRs are identified and the implications for unwanted side-effects, as well as for repurposing opportunities, discussed.
PMCID: PMC3717414  PMID: 21851335
GPCR network; ligand similarity; target profile; adverse effects; drug repositioning
9.  Combination of Biological Screening in a Cellular Model of Viral Latency and Virtual Screening Identifies Novel Compounds That Reactivate HIV-1 
Journal of Virology  2012;86(7):3795-3808.
Although highly active antiretroviral therapy (HAART) has converted HIV into a chronic disease, a reservoir of HIV latently infected resting T cells prevents the eradication of the virus from patients. To achieve eradication, HAART must be combined with drugs that reactivate the dormant viruses. We examined this problem in an established model of HIV postintegration latency by screening a library of small molecules. Initially, we identified eight molecules that reactivated latent HIV. Using them as templates, additional hits were identified by means of similarity-based virtual screening. One of those hits, 8-methoxy-6-methylquinolin-4-ol (MMQO), proved to be useful to reactivate HIV-1 in different cellular models, especially in combination with other known reactivating agents, without causing T-cell activation and with lower toxicity than that of the initial hits. Interestingly, we have established that MMQO produces Jun N-terminal protein kinase (JNK) activation and enhances the T-cell receptor (TCR)/CD3 stimulation of HIV-1 reactivation from latency but inhibits CD3-induced interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-α) gene transcription. Moreover, MMQO prevents TCR-induced cell cycle progression and proliferation in primary T cells. The present study documents that the combination of biological screening in a cellular model of viral latency with virtual screening is useful for the identification of novel agents able to reactivate HIV-1. Moreover, we set the bases for a hypothetical therapy to reactivate latent HIV by combining MMQO with physiological or pharmacological TCR/CD3 stimulation.
doi:10.1128/JVI.05972-11
PMCID: PMC3302487  PMID: 22258251
11.  Myxobacteria: natural pharmaceutical factories 
Myxobacteria are amongst the top producers of natural products. The diversity and unique structural properties of their secondary metabolites is what make these social microbes highly attractive for drug discovery. Screening of products derived from these bacteria has revealed a puzzling amount of hits against infectious and non-infectious human diseases. Preying mainly on other bacteria and fungi, why would these ancient hunters manufacture compounds beneficial for us? The answer may be the targeting of shared processes and structural features conserved throughout evolution.
doi:10.1186/1475-2859-11-52
PMCID: PMC3420326  PMID: 22545867
Myxobacteria; Natural products; Drug discovery; Chemical space
12.  A Chemocentric Approach to the Identification of Cancer Targets 
PLoS ONE  2012;7(4):e35582.
A novel chemocentric approach to identifying cancer-relevant targets is introduced. Starting with a large chemical collection, the strategy uses the list of small molecule hits arising from a differential cytotoxicity screening on tumor HCT116 and normal MRC-5 cell lines to identify proteins associated with cancer emerging from a differential virtual target profiling of the most selective compounds detected in both cell lines. It is shown that this smart combination of differential in vitro and in silico screenings (DIVISS) is capable of detecting a list of proteins that are already well accepted cancer drug targets, while complementing it with additional proteins that, targeted selectively or in combination with others, could lead to synergistic benefits for cancer therapeutics. The complete list of 115 proteins identified as being hit uniquely by compounds showing selective antiproliferative effects for tumor cell lines is provided.
doi:10.1371/journal.pone.0035582
PMCID: PMC3338416  PMID: 22558171
13.  Automatic Filtering and Substantiation of Drug Safety Signals 
PLoS Computational Biology  2012;8(4):e1002457.
Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions.
Author Summary
Adverse drug reactions (ADRs) constitute a major cause of morbidity and mortality worldwide. Due to the relevance of ADRs for both public health and pharmaceutical industry, it is important to develop efficient ways to monitor ADRs in the population. In addition, it is also essential to comprehend why a drug produces an adverse effect. To unravel the molecular mechanisms of ADRs, it is necessary to consider the ADR in the context of current biomedical knowledge that might explain it. Nowadays there are plenty of information sources that can be exploited in order to accomplish this goal. Nevertheless, the fragmentation of information and, more importantly, the diverse knowledge domains that need to be traversed, pose challenges to the task of exploring the molecular mechanisms of ADRs. We present a novel computational framework to aid in the collection and exploration of evidences that support the causal inference of ADRs detected by mining clinical records. This framework was implemented as publicly available tools integrating state-of-the-art bioinformatics methods for the analysis of drugs, targets, biological processes and clinical events. The availability of such tools for in silico experiments will facilitate research on the mechanisms that underlie ADR, contributing to the development of safer drugs.
doi:10.1371/journal.pcbi.1002457
PMCID: PMC3320573  PMID: 22496632
14.  iPHACE: integrative navigation in pharmacological space 
Bioinformatics  2010;26(7):985-986.
Summary: The increasing availability of experimentally determined binding affinities for drugs on multiple protein targets requires the design of specific mining and visualization tools that graphically integrate chemical and biological data in an efficient environment. With this aim, we developed iPHACE, an integrative web-based tool to navigate in the pharmacological space defined by small molecule drugs contained in the IUPHAR-DB, with additional interactions present in PDSP. Extending beyond traditional querying and filtering tools, iPHACE offers a means to extract knowledge from the target profile of drugs as well as from the drug profile of protein targets.
Availability: iPHACE is available at http://cgl.imim.es/iphace/ (EU site) and http://agave.health.unm.edu/iphace/ (US mirror)
Contact: jmestres@imim.es
doi:10.1093/bioinformatics/btq061
PMCID: PMC2844997  PMID: 20156991
15.  Applied information retrieval and multidisciplinary research: new mechanistic hypotheses in Complex Regional Pain Syndrome 
Background
Collaborative efforts of physicians and basic scientists are often necessary in the investigation of complex disorders. Difficulties can arise, however, when large amounts of information need to reviewed. Advanced information retrieval can be beneficial in combining and reviewing data obtained from the various scientific fields. In this paper, a team of investigators with varying backgrounds has applied advanced information retrieval methods, in the form of text mining and entity relationship tools, to review the current literature, with the intention to generate new insights into the molecular mechanisms underlying a complex disorder. As an example of such a disorder the Complex Regional Pain Syndrome (CRPS) was chosen. CRPS is a painful and debilitating syndrome with a complex etiology that is still unraveled for a considerable part, resulting in suboptimal diagnosis and treatment.
Results
A text mining based approach combined with a simple network analysis identified Nuclear Factor kappa B (NFκB) as a possible central mediator in both the initiation and progression of CRPS.
Conclusion
The result shows the added value of a multidisciplinary approach combined with information retrieval in hypothesis discovery in biomedical research. The new hypothesis, which was derived in silico, provides a framework for further mechanistic studies into the underlying molecular mechanisms of CRPS and requires evaluation in clinical and epidemiological studies.
doi:10.1186/1747-5333-2-2
PMCID: PMC1871567  PMID: 17480215
16.  PharmaTrek: A Semantic Web Explorer for Open Innovation in Multitarget Drug Discovery 
Molecular Informatics  2012;31(8):537-541.
doi:10.1002/minf.201200070
PMCID: PMC3573647  PMID: 23548981
Semantic web; Chemogenomics; Target profile; Polypharmacology

Results 1-16 (16)