Identifying targets for drug discovery using bioinformatics

BACKGROUNd: Drug discovery is the process of discovering and designing drugs, which includes target identification, target validation, lead identification, lead optimization and introduction of the new drugs to the public. This process is very important, involving analyzing the causes of the diseases and finding ways to tackle them. OBJECTIVE: The problems we must face include: i) that this process is so long and expensive that it might cost millions of dollars and take a dozen years; and ii) the accuracy of identification of targets is not good enough, which in turn delays the process. Introducing bioinformatics into the drug discovery process could contribute much to it. Bioinformatics is a booming subject combining biology with computer science. It can explore the causes of diseases at the molecular level, explain the phenomena of the diseases from the angle of the gene and make use of computer techniques, such as data mining, machine learning and so on, to decrease the scope of analysis and enhance the accuracy of the results so as to reduce the cost and time. METHODS: Here we describe recent studies about how to apply bioinformatics techniques in the four phases of drug discovery, how these techniques improve the drug discovery process and some possible difficulties that should be dealt with. Results: We conclude that combining bioinformatics with drug discovery is a very promising method although it faces many problems currently.     

Design,synthesis and biological evaluation of novel thiophene and theinopyrimidine derivatives as anticancer agents

Some novel thiophene and theinopyrimidine derivatives have been synthesized. Their structures were confirmed by elemental analyses, infrared, ¹H NMR, ¹³C NMR and mass spectral data. All the target compounds were screened against liver adenocarcinoma (HepG2) cell line. Compounds 9c, 9b, 10b, and 7c in a sequent were the most potent compounds between all the test compounds with IC₅₀ values [0.01063, 0.01158, 0.01729, 0.01957?µM], respectively. Compounds 13b, 7b, 5d, 9a, 8a, and 11b showed higher activity with IC₅₀ values ranged from 0.02231 to 0.03673?µM when compared with 5-flurouracil (A) as a reference drug (IC₅₀?=?0.0384?µM).     

A comparison of post‐stroke hypertension medication use between US Stroke Belt and Non‐Stroke Belt residents

Although hypertension is a contributing factor to higher stroke occurrence in the Stroke Belt, little is known about post‐stroke hypertension medication use in Stroke Belt residents. Through the use of national Behavioral Risk Factor Surveillance System surveys from 2015, 2017, and 2019; we compared unadjusted and adjusted estimates of post‐stroke hypertension medication use by Stroke Belt residence status. Similar levels of post‐stroke hypertension medication use were observed between Stroke Belt residents (OR: 1.09, 95% CI: 0.89, 1.33) and non‐Stroke Belt residents. After adjustment, Stroke Belt residents had 1.14 times the odds of post‐stroke hypertension medication use (95% CI: 0.92, 1.41) compared to non‐Stroke Belt residents. Findings from this study suggest that there is little difference between post‐stroke hypertension medication use between Stroke Belt and non‐Stroke Belt residents. However, further work is needed to assess whether use of other non‐medicinal methods of post‐stroke hypertension control differs by Stroke Belt residence status.     

Considerations for pre‐transfusion immunohaematology testing in patients receiving the anti‐CD38 monoclonal antibody daratumumab for the treatment of multiple myeloma

In recent years, the anti‐CD38 monoclonal antibody daratumumab (Darzalex; Janssen‐Cilag Pty Ltd) has been shown to be highly efficacious in relapsed and refractory multiple myeloma, with the final results of treatment in newly diagnosed patients awaited. Despite awareness of the potential interference of daratumumab in pre‐transfusion immunohaematology testing during phase I and II clinical studies, there was a degree of unpreparedness in the community upon the introduction of this drug into the clinics, particularly the impact that it has on the operational processes in hospital transfusion laboratories and timely issue of red blood cells (RBCs). Anti‐CD38 interference in pre‐transfusion immunohaematology tests is a particular problem in patients being treated with daratumumab for multiple myeloma as many will require RBC transfusions during their disease treatment. Panagglutination caused by anti‐CD38 monoclonal antibody during the indirect antiglobulin test may mask the presence of a clinically significant RBC alloantibody in the patient’s plasma during the antibody screen and identification process, which may be overlooked, particularly in urgent situations, subsequently resulting in a delayed or acute haemolytic transfusion reaction. Here, we summarise daratumumab’s effects on pre‐transfusion immunohaematology testing and its impact on clinical practice and make practical recommendations based on a consensus from medical and scientific transfusion experts and myeloma specialists on behalf of the Australian and New Zealand Society of Blood Transfusion and Myeloma Scientific Advisory Group to Myeloma Australia, respectively.     

Prevalence of psychopathology in bipolar high-risk offspring and siblings: a meta-analysis

This meta-analysis aimed to update existing data on the comparison of prevalence rates of psychopathology primarily among offspring with at least one parent with bipolar disorder (BD) and offspring of parents without psychiatric illness. Seventeen studies were derived from a systematic search of PsychInfo, Medline, Scopus and Embase. Inclusion criteria were use of a control offspring group, standardized diagnostic procedures and reporting of clear frequency data. Risk of psychopathology was estimated by aggregating frequency data from selected studies. Compared to control offspring, high-risk BD offspring are nine times more likely to have a bipolar-type disorder, almost two and a half times more likely to develop a non-BD affective disorder and over two times more likely to develop at least one anxiety disorder. High-risk offspring also showed a significant increased risk of other non-mood psychopathology such as attention deficit hyperactivity disorder (ADHD), any type of behavioral disorder and substance use disorder (SUDs). Risk of developing a broad range of affective and non-affective psychopathology is significantly higher in high-risk BD offspring. Identifying clinical presentations of this genetically high-risk cohort is important in establishing appropriate preventative treatment.     

Prognostic markers and long-term outcomes in ductal carcinoma in situ of the breast treated with excision alone

BACKGROUND:

Increased use of breast cancer screening has led to an increase in the number of diagnosed cases of ductal carcinoma in situ (DCIS). However, there is no definite way to predict progression or recurrence of DCIS. We analyzed the significance of biological markers and tumor characteristics in predicting recurrence in a large series of DCIS patients with long‐term follow‐up treated with breast conservation surgery (BCS) alone.

METHODS:

Clinical and pathological data were analyzed for 141 patients who underwent BCS for DCIS. All had negative surgical margins. Using local disease recurrence as an endpoint, we sought to determine the prognostic significance of several histopathological characteristics (tumor size, presence of necrosis, and subtype) and biological markers (estrogen receptor, progesterone receptor, and Her‐2/neu.)

RESULTS:

At a median follow‐up of 122 months (maximum follow‐up, 294 months), 60 recurrences occurred, with a median time to recurrence of 191 months. On multivariate analysis, Her‐2 positivity (3+) was found to be significantly associated with reduced time to tumor recurrence (P = .028). Tumor size and higher grade were marginally statistically significant (P = .099, P = .070). Neither necrosis nor tumor pathological characteristics were found to be significantly related to time to disease recurrence.

CONCLUSIONS:

Our results suggested that status of Her‐2/neu, larger tumor size, and higher nuclear grade were significantly correlated with time to tumor recurrence in patients treated with BCS alone. Using logistical analyses, no significant correlation was found between tumor pathological characteristics and disease recurrence. Cancer 2011. © 2011 American Cancer Society.