Modern Approach For Drug Design Is Laid On The Principle Of `` Big Numbers ``

This paper hopes to share insight into the steps that are taken by companies, and the strenuous process behind developing an effective new drug.

Biotechnology, which involves understanding the complex of chemistry of life, has developed potential photochemical drug for the treatment of lot of diseases. Right

Pharmacogenomics, a component of precision medicine, is the study of how genes affect a person’s response to particular drugs. It involves a combination of pharmacology and genomics, to manufacture medication and doses that are customized to fulfill the variations found in people’s genes. (Reference 2016)

High throughput screening (HTS) is essential in the process of finding a potential drug candidate, and automation is key for a good screen both in terms of robustness and reproducibility.

The process relies on taking libraries of known compounds and assaying them for relevant biological activity. HTS has been widely used in modern drug discovery for conventional targets, showing its validity as a discovery approach.13, 29-31 The major issue impeding HTS as an iPPI discovery method is the nature of current libraries. Due to the fact pharmaceutical companies have mostly focused on modulating traditional targets such as enzymes, their drug libraries contain a large amount legacy compounds which are inactive towards PPIs due to the major structural differences discussed previously.32-35 This bias of current drug libraries was highlighted by Majmudar in 2012 when his team compared results from a standard drug library to one consisting of natural product molecules, when assayed against the CBP/p300 interface. The team found that the natural product library showed three successful hits from 15,000 compounds, whereas the library of 5000 synthetic drugs returned no hits.36 This shows that indiscriminately testing libraries of compounds for activity against PPIs is not the most effective method of discovery. As has been highlighted, many of the pre-existing libraries are focused more towards enzyme and GCPRs and so do not possess the required structural

Fig. 3- Glucose in the tubular epithelial is transported down a concentration graident via GLUT1, across the basolateral membrane into portal circulation. Glucose maximum absorption is 375 mg/min. Once that gradient has been crossed glucose is excreted in urine due to the inabilty of SGLT2 transporters ability to reabsorb [6]

Glucose transporter 4 (GLUT4) is a membrane protein glucose transporter that facilitates the uptake of glucose in the skeletal muscle. Hence upregulation of GLUT4 can help in increasing the glucose uptake by the skeletal muscle. CA treatment on C2C12 cells significantly increased the GLUT4 expression in a dose dependent manner without altering glucose metabolism[4, 5]. Membrane fractions of the skeletal muscles were isolated and from male wistar rats which were treated with streptozotocin to induce diabetes and then treated with 20mg/kg body weight for 60 days with CA. GLUT4 levels in the muscles isolated from the CA treated rats restored to 73.1% as compared to the untreated diabetic rats which had 42.8% levels of GLUT4. Deficiency of insulin in diabetic rats results in decreased translocation of GLUT4. Levels of GLUT4 in healthy control rats was considered to be 100%[6]. Peroxisome proliferator-activated response (PPAR) gamma is known to increase insulin sensitivity, hence greater expression of these might help in controlling glucose levels[7]. Upregulation of these helps in improving insulin resistance and insulin signaling in muscles as well as adipose tissue[8]. In-vitro study done on TSA201 cell lines showed that CA was able to decrease the resistance to insulin by up-regulating genes in adipocytes by activating PPAR delta and PPAR

In addition to endothelial cells, it depends on continuous complexes of tight junctions that seals and prevent all but a few substances from squeezing between barrier cells. A recent study stated that in order for substances to pass through the brain, specific carrier mediated transport systems assist transport of nutrients such as glucose, galactose, small peptides, and amines binds to specific membrane protein

SCREENING CASCADE DESIGN TO IDENTIFY A DRUG CANDIDATE FOR CHOSEN TARGET THAT AIMS TO WORK IN HUMAN PATIENT

We marked the drugs and small compound molecules in the intersection of transcriptomic and cell morphological profiles, and collectively, transcriptomic ($T$) and cell morphological ($C$) profiles of 9515 drugs and small compound molecules were provided as a back-end data for our proposed pipeline. Finally, we standardized the transcriptomic and cell morphological profiles via \textit{unitization with zero minimum} ($\frac{x-minimum}{range}$), where $x$ is a non-missing values in a vector of numerical values representing changes of a variable.

HTS is simple, rapid, high efficiency, less expensive and valuable in discover ligand for enzymes, receptors (GPCR, ion-channels). High throughput technology has emerged over the last few years as an important tool for drug discovery and lead optimization. HTS comprises the screening of large chemical libraries for pharmacological activity against biological targets via the use of robotics, miniaturized assays and large-scale data analysis. The purpose of HTS is to identify the hits, active on the target and that can then be further converted by chemical optimization to a genuine lead which emerges as candidate for clinical development. HTS is defined by the number of compounds tested to be in the range of 10 000–100 000 per day, uHTS is defined by screening numbers in excess of 100 000 data points generated per day. (Lorenz M Mayr and Dejan Bojanic, 2009).Various technologies for assay miniaturization, lab automation and robotics enable testing of chemical compounds in biological systems by means of high-throughput screening (HTS) and ultra-highthroughput screening (uHTS). HTS assays are performed in "automation-friendly" micro-titer plates with a 96, 384 or 1536 well format. Assays today are commonly run in 1536-well plate format with low μL to high nL volumes per well. To increase speed and efficiency, ultra high-throughput screening (uHTS) utilizing

Development of drugs with high potency and inhibitory activity against specific activating mutation, while showing significantly less activity against wild type mutations, made testing specific sensitizing mutation necessary. (1) (EGFR) T790M mutation a successful example of a biomarker for non-small cell lung cancer (NSCLC) treatment with Osimertinib that gained a wide acceptance in clinical practice in Europe and US (), One question that needs to be asked, however, is whether testing for similar mutations in different cancer will be of clinical value. an unknown subpopulation of patients with CRC will have an activating EGFR mutation, such as L858R, which is thought to activate the receptor constitutively, regardless of ligand status promoting cellular proliferation and growth. in patients with colorectal cancer, Targeting activated EGFR, hypothetically, will lead to growth inhibition of cancer cell dependent on the oncogenic drive of sensitising EGFR mutation.

The various lead compounds can be initially tested and virtual screened by high-throughput screenings (HTS) to evaluate their properties in biochemical reactions, and then the lead compounds will be optimized through altering their molecular structure. Several physicochemical properties and pharmacokinetics properties of the lead compounds will be established, such as lipophilicity, solubility, ionization, molecular size and H-bonding. The process of lead optimization can not only improves lead compounds’ physicochemical properties, but also makes them more effective and safer. Simultaneously, medicinal chemists begin to consider about chemical manufacture and control (CMC), such as synthesis, formulation, delivery mechanism and large-scale manufacturing. The optimized lead compound could ultimately evolve into a new drug candidate. The function of pre-clinical research is to assess all of the physicochemical and pharmacokinetics parameters prior to clinical trials. Or, to put it another way, whether the lead compound is safe enough to move on to clinical trials depends on pre-clinical research. For example, pharmaceutical researchers carry out pharmacokinetics (PK) testing which involves absorption, distribution, metabolism, excretion (ADME), and toxicology to estimate the safety starting dose through in vitro and in vivo testing. After these complicated and rigorous pre-clinical trials, scientists have

One of the biggest challenges in drug research— or in any field—is to let go of ideas that are no longer promising and to move on to brighter prospects that aren’t being given enough attention. When new hire Lee Babiss arrived from archrival Glaxo to head preclinical research, he preached a simple message: Fail fast. He knew that the best hope of finding the right new drugs was to spend less time on dead-ends. Screening was needed to sift though

The research and development of the pharmaceutical industry is very important as the industry relies on it to develop new products to maintain and sustain the growth of the industry (ALRC 2014). According to the Australian Government Law Reform Commission, every year, the total spending in research and development in pharmaceutical industry, which includes drug discovery, pre-clinical testing and clinical trials on drugs is around $300 million (ALRC 2014). Mergers and acquisitions are intensifying in the global pharmaceutical industry, especially over the last 10 years. With factors like exorbitant research and development costs, the relatively shorter product life cycles, and the rarity of discovering a new life-changing drug acting as catalysts, leading pharmaceutical companies now have more cause to step out and look for external collaboration. This results in an increasing number of smaller biotechnology companies merging with bigger pharmaceutical companies (The