Molecular Genetic Techniques in Biomarker Analysis Relevant for Drugs Centrally Approved in Europe.
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ABSTRACT:
SUBMITTER: Huebner T
PROVIDER: S-EPMC8766366 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chemical space maps help visualize similarities within molecular sets. However, there are many different molecular similarity measures resulting in a confusing number of possible comparisons. To overcome this limitation, we exploit the fact that tools designed for reaction informatics also work for alchemical processes that do not obey Lavoisier's principle, such as the transmutation of lead into gold. We start by using the differential reaction fingerprint (DRFP) to create tree-maps (TMAPs) representing the chemical space of pairs of drugs selected as being similar according to various molecular fingerprints. We then use the Transformer-based RXNMapper model to understand structural relationships between drugs, and its confidence score to distinguish between pairs related by chemically feasible transformations and pairs related by alchemical transmutations. This analysis reveals a diversity of structural similarity relationships that are otherwise difficult to analyze simultaneously. We exemplify this approach by visualizing FDA-approved drugs, EGFR inhibitors, and polymyxin B analogs.
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Project description:AimsCancer drugs are increasingly approved through expedited regulatory pathways including the European conditional marketing authorization (CMA). Whether, when taking CMA post-approval confirmatory trials into account, the level of evidence and clinical benefit between CMA and standard approved (SMA) drugs differs remains unknown.MethodsWe identified all CMA cancer indications converted to SMA in 2006-2020 and compared these to similar SMA indications with regard to pivotal trial and CMA post-approval confirmatory trial design, outcomes and demonstrated clinical benefit (per the European Society for Medical Oncology Magnitude of Clinical Benefit Scale). We tested for differences in clinical benefit and whether substantial clinical benefit was demonstrated. To account for the clinical benefit of unconverted CMA indications, we performed sensitivity analyses.ResultsWe included 15 SMA and 15 converted CMA cancer indications (17 remained unconverted). Approval of 11 SMA (73%) and four CMA indications (27%) was supported by a controlled trial. Improved overall survival (OS) was demonstrated for four SMA indications (27%). Improved quality of life (QoL) was demonstrated for three SMA (20%) and one CMA indication(s) (7%). Of subsequent CMA post-approval confirmatory trials, 11 were controlled (79%), one demonstrated improved OS (7%) and five improved QoL (36%). After conversion, CMA indications were associated with similar clinical benefit (P = .31) and substantial clinical benefit as SMA indications (risk ratio 1.4, 95% confidence interval 0.57-3.4).ConclusionWhile CMA cancer indications are initially associated with less comprehensive evidence than SMA indications, levels of evidence and clinical benefit are similar after conversion from CMA to SMA.
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Project description:For oncology drugs that were approved by the US Food and Drug Administration (FDA) and required pharmacogenomic biomarker testing, we describe 1) the use of enrichment (biomarker-positive patients) and a randomized controlled design by pre-approval trials and 2) the treatment-by-biomarker interaction. From the 137 drugs included in the FDA table, we selected the 22 oncology drugs with required genetic testing in their labels. These drugs corresponded to 35 approvals supported by 80 clinical studies included in the FDA medical officer reviews of efficacy. For two thirds of approvals (24/35, 69%), all clinical studies were restricted to biomarker-positive patients (enriched). Among the 11 remaining approvals with at least one non-enriched trial, for five approvals, the non-enriched studies were non-randomized. The treatment-by-biomarker interaction was statistically significant for three approvals and missing for two. Among the six approvals with a non-enriched randomized controlled trial, three featured a statistically significant treatment-by-biomarker interaction (p?<?0.10), for an enhanced treatment effect in the biomarker-positive subgroup. For two thirds of FDA approvals of anticancer agents, the requirement for predictive biomarker testing was based on clinical development restricted to biomarker-positive patients. We found only few cases with clinical evidence that biomarker-negative patients would not benefit from treatment.
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Project description:Arenaviruses, Junin and Machupo are pathogenic viruses in regions of South America including Argentina and Bolivia causing haemorrhagic fever among humans. They have been transmitted to humans through mouse causing chronic illness with high mortality. Therefore, it is of interest to acquittance the molecular docking analysis data of FDA approved drugs with the glycoprotein from Junin and Machupo viruses for consideration in drug discovery. Thus, we report the optimal binding features of MK-3207 and Dihydro ergotamine with the protein target for further validation and consideration.
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Project description:The discovery of novel anticancer drugs is critical for the pharmaceutical research and development, and patient treatment. Repurposing existing drugs that may have unanticipated effects as potential candidates is one way to meet this important goal. Systematic investigation of efficient anticancer drugs could provide valuable insights into trends in the discovery of anticancer drugs, which may contribute to the systematic discovery of new anticancer drugs.In this study, we collected and analyzed 150 anticancer drugs approved by the US Food and Drug Administration (FDA). Based on drug mechanism of action, these agents are divided into two groups: 61 cytotoxic-based drugs and 89 target-based drugs. We found that in the recent years, the proportion of targeted agents tended to be increasing, and the targeted drugs tended to be delivered as signal drugs. For 89 target-based drugs, we collected 102 effect-mediating drug targets in the human genome and found that most targets located on the plasma membrane and most of them belonged to the enzyme, especially tyrosine kinase. From above 150 drugs, we built a drug-cancer network, which contained 183 nodes (150 drugs and 33 cancer types) and 248 drug-cancer associations. The network indicated that the cytotoxic drugs tended to be used to treat more cancer types than targeted drugs. From 89 targeted drugs, we built a cancer-drug-target network, which contained 214 nodes (23 cancer types, 89 drugs, and 102 targets) and 313 edges (118 drug-cancer associations and 195 drug-target associations). Starting from the network, we discovered 133 novel drug-cancer associations among 52 drugs and 16 cancer types by applying the common target-based approach. Most novel drug-cancer associations (116, 87%) are supported by at least one clinical trial study.In this study, we provided a comprehensive data source, including anticancer drugs and their targets and performed a detailed analysis in term of historical tendency and networks. Its application to identify novel drug-cancer associations demonstrated that the data collected in this study is promising to serve as a fundamental for anticancer drug repurposing and development.
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Project description:Developing a safe and effective antiviral treatment takes a decade, however, when it comes to the coronavirus disease (COVID-19), time is a sensitive matter to slow the spread of the pandemic. Screening approved antiviral drugs against COVID-19 would speed the process of finding therapeutic treatment. The current study examines commercially approved drugs to repurpose them against COVID-19 virus main protease using structure-based in-silico screening. The main protease of the coronavirus is essential in the viral replication and is involved in polyprotein cleavage and immune regulation, making it an effective target when developing the treatment. A Number of approved antiviral drugs were tested against COVID-19 virus using molecular docking analysis by calculating the free natural affinity of the binding ligand to the active site pocket and the catalytic residues without forcing the docking of the ligand to active site. COVID-19 virus protease solved structure (PDB ID: 6LU7) is targeted by repurposed drugs. The molecular docking analysis results have shown that the binding of Remdesivir and Mycophenolic acid acyl glucuronide with the protein drug target has optimal binding features supporting that Remdesivir and Mycophenolic acid acyl glucuronide can be used as potential anti-viral treatment against COVID-19 disease.
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Project description:For many authorized drugs, accumulating scientific evidence supports testing for predictive biomarkers to apply personalized therapy and support preventive measures regarding adverse drug reactions and treatment failure. Here, we review cytogenetic and biochemical genetic testing methods that are available to guide therapy with drugs centrally approved in the European Union (EU). We identified several methods and combinations of techniques registered in the Genetic Testing Registry (GTR), which can be used to guide therapy with drugs for which pharmacogenomic-related information is provided in the European public assessment reports. Although this registry provides information on genetic tests offered worldwide, we identified limitations regarding standard techniques applied in clinical practice and the information on test validity rarely provided in the according sections.
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Project description:PurposeTo optimize and streamline molecular genetics techniques in diagnosing choroideremia (CHM).MethodsPCR primers were designed for exons 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 15 of the CHM gene. Each PCR protocol was optimized so that all exons could be amplified with the same component ratio and PCR conditions. Sense and antisense primers were tested for their ability to be used as sequencing primers. Fibroblast cells were cultured, and an immunoblot analysis was performed to detect the presence or absence of Rab escort protein 1 (REP-1) in a suspected CHM patient sample when no mutation was detected with sequencing. Multiplex ligation-dependent probe amplification (MLPA) of the CHM gene was performed and used to detect deletions and duplications in affected males and female carriers. RNA analysis using cDNA was used to detect the presence or absence of the CHM transcript and to search for splice defects.ResultsThe newly designed PCR primers allow for more efficient PCR preparation and sequencing to detect point mutations in affected males and female carriers. Immunoblot successfully detects the absence of REP-1 in a CHM patient. MLPA identifies deletions and duplications spanning multiple exons in the CHM gene. RNA analysis aids in detecting splice variants.ConclusionsThe development of new molecular biology techniques and ongoing optimization of existing methods allows for an improved integrated approach to confirm CHM diagnosis and carrier status in consideration of patient family history and available patient sample materials. CHM can be confirmed with an immunoblot assay. To detect the molecular cause of CHM, an examination of the genomic DNA or the mRNA must be performed. Presymptomatic carriers with no identifiable fundus signs can be identified only through molecular analysis of genomic DNA or through quantitative assays.
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Project description:Protein kinases are key enzymes that catalyze the covalent phosphorylation of substrates via the transfer of the γ-phosphate of ATP, playing a crucial role in cellular proliferation, differentiation, and various cell regulatory processes. Due to their pivotal cellular role, the aberrant function of kinases has been associated with cancers and many other diseases. Consequently, competitive inhibition of the ATP binding site of protein kinases has emerged as an effective means of curing these diseases. Decades of intense development of protein kinase inhibitors (PKIs) resulted in 71 FDA-approved PKI drugs that target dozens of protein kinases for the treatment of various diseases. How do FDA-approved protein kinase inhibitor PKI drugs compete with ATP in their own binding pocket? This is the central question we attempt to address in this work. Based on modes of non-bonded interactions and their calculated interaction strengths by means of the advanced double hybrid DFT method B2PLYP, the molecular recognition of PKI drugs in the ATP-binding pockets was systematically analyzed. It was found that (1) all the FDA-approved PKI drugs studied here form one or more hydrogen bond(s) with the backbone amide N, O atoms in the hinge region of the ATP binding site, mimicking the adenine base; (2) all the FDA-approved PKI drugs feature two or more aromatic rings. The latter reach far and deep into the hydrophobic regions I and II, forming multiple CH-π interactions with aliphatic residues L(3), V(11), A(15), V(36), G(51), L(77) and π-π stacking interactions with aromatic residues F(47) and F(82), but ATP itself does not utilize these regions extensively; (3) all FDA-approved PKI drugs studied here have one thing in common, i.e., they frequently formed non-bonded interactions with a total of 12 residues L(3),V(11), A(15), K(17), E(24),V(36),T(45), F(47), G(51), L(77), D(81) and F(82) in the ATP binding. Many of those 12 commonly involved residues are highly conserved residues with important structural and catalytic functional roles. K(17) and E(24) are the two highly conserved residues crucial for the catalytic function of kinases. D(81) and F(82) belong to the DFG motif; T(45) was dubbed the gate keeper residue. F(47) is located on the hinge region and G(51) sits on the linker that connects the hinge to the αD-helix. It is this targeting of highly conserved residues in protein kinases that led to promiscuous PKI drugs that lack selectivity. Although the formation of hydrogen bond(s) with the backbone of the hinge gives PKI drugs the added binding affinity and the much-needed directionality, selectivity is sacrificed. That is why so many FDA-approved PKI drugs are known to have multiple targets. Moreover, off-target-mediated toxicity caused by a lack of selectivity was one of the major challenges facing the PKI drug discovery community. This work suggests a road map for future PKI drug design, i.e., targeting non-conserved residues in the ATP binding pocket to gain better selectivity so as to avoid off-target-mediated toxicity.
| S-EPMC9611543 | biostudies-literature
Project description:AIMS:Rising antimicrobial resistance (AMR) is a global health crisis. India has among the highest resistance rates and antibiotic consumption internationally. Extensive use of fixed-dose combination (FDC) antibiotics and of unapproved formulations are claimed contributory factors but there has been no systematic examination of formulations or volumes sold. The aim of the present study was to investigate the regulatory approval status and sales volumes of systemic antibiotics marketed in India. METHODS:This was an ecological study using regulatory records in India, the UK and the US to determine the approval status in each country of systemic antibiotic FDCs and single-drug formulations (SDFs) sold in India. Pharmatrac® sales data were used to determine the formulations and volumes sold (2007-2012), branded-product numbers and manufacturers. RESULTS:Of 118 systemic antibiotic FDC formulations sold in India, 43 (36%) were approved but 75 (64%) had no record of regulatory approval; four (3%) formulations were approved in the UK and/or US. Almost half of formulations (58/118; 49%) comprised dual antimicrobials, most unapproved in India (43/58; 74%), and many were pharmacologically problematic. In contrast, 80/86 (93%) SDFs were approved in India and over two-thirds in the UK and/or US. Total antibiotic sales increased by 26%, from 2056 million units (2007-08) to 2583 million units (2011-12). FDC sales rose by 38% vs. 20% for SDFs. By 2011-12, FDCs comprised one-third of sales (872 million units). Over one-third of FDCs sold (300.26 million units; 34.5%) were of unapproved formulations. Multinational companies manufactured unapproved formulations and accounted for 19% of all FDC and SDF sales annually. CONCLUSIONS:Sales in India of antibiotic FDCs, including unapproved formulations, are rising. In the context of increasing AMR rates nationally and globally, unapproved antibiotic FDCs undermine India's national AMR strategy and should be banned from sale.
| S-EPMC6303201 | biostudies-literature