💊 Drug Discovery and Development Process | Hit Discovery via High Throughput Screening

R E A D M E : PLEASE REFER TO THE CORRECTED VERSION:    • 💊 DRUG DISCOVERY AND DEVELOPMENT via High ...  

CORRECTIONS:
At 10:29: Z factor and Z prime are two different calculations.
Z factor is calculated during the actual assay stage (primary screen) to determine if any of the compounds exhibit interesting biological properties e.g 3 standard deviations above the Mean. The calculation is referenced to a signal from known drugs with known percent effects against which you adjust your unknown compounds

Z prime can be calculated before the pilot or primary screen. It looks at the robustness of the assay. The calculation is based only on the positive and negative controls.

1:09: Lead Discovery should read HIT DISCOVERY via High Throughput Screening


//Time stamps:

1:30 -- Stakeholders in the drug discovery and development process
1:50 -- Target Identification

8:00 -- Steps in High Throughput Screening (Z prime calculation, signal to background, signal to noise, z factor for picking 'hits')

10:30 -- Pilot screen
11:20 -- Primary Screen
12:40 -- Picking 'Hits'
13:00 -- Counter Screen
15:00 -- Concentration response/dose response curves
17:00 -- Hit to Lead

The updated version:    • 💊 DRUG DISCOVERY AND DEVELOPMENT via High ...  

//Background
The process of drug/medicine discovery and development involves finding chemical entities that interacts with biological targets. The search begins with identification of biological targets (target identification) involved in a disease and validating the target through experimentation.

Following target identification and validation, the expertise and services of High Throughput Screening laboratories can be sought to identify small molecule compounds that interact with the target (Hit Discovery). Keep in mind that High Throughput Screening is not the only way of initiating drug/medicine discovery. Other approaches include Structure-Based Design, Virtual Screening, Informatics Mining, Rational Design and Affinity Screening. These alternative approaches can be combined with HTS.

The High Throughput Screening part of drug/medicine discovery involves several steps:

Firstly, there is the transfer of the biological assay into a miniaturised format that is amenable to high- throughput screening (HTS). The assay development for HTS is a huge part of the process and involves things like volume optimisation, DMSO tolerance checks, cross titrations of interacting assay components amongst others. Crucial parameters such as signal to background, signal to noise, Z' factor are checked at this point.

Following assay transfer/development, a selection of compounds are assayed in a Pilot Screen. The pilot screen aims to identify hit rates and adjust compound screening concentrations if needed. Once again, signal to background, signal to noise, Z prime factor (Z') parameters are monitored. An additional parameter - Z factor - which monitors the hit rate of compounds is assessed before embarking on a Primary Screen. In the Primary Screen, hundreds of thousands of compounds are assayed to find promising molecules.

Compounds that come up as potential interactors with your target during the Primary Screen, are put through a Counter Screen to confirm that the signal was not due to interference with the assay readout technology. Counter screens weed out 'hits' that are falsely reported. 10-point serial dilutions of each compound is also used to generate concentration/dose response curves to measure the potency of the compound(s) before flagging it as a 'hit'.

Confirmed hits are assayed via additional experiments that use a different readout (orthogonal assays) before they are considered as Leads.

Lead compounds are optimised to become more drug like - with the help of medicinal chemists - and then tested in animal models to assess appropriate safety and efficacy profiles. Human clinical trials are performed to assess efficacy and safety. Only when a compound passes this stage, is it considered a drug candidate.

//VIDEO MENTIONED
link to Statistics Made Accessible for explanation of standard deviation:
   • Statistics Made Very Accessible  

✨Special thanks to past colleague Pat Novello for all her valuable input! ✨

Stay tuned for part 2 which clarifies the process in more details.

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//MUSIC
Music: Shine by Joakim Karud
http://joakimkarud.com/use-my-music/



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