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Printable Handouts
Navigable Slide Index
- Introduction
- Outline of the presentation
- What is Binding Kinetics?
- The simple case of binding kinetics
- Binding kinetics in a web of interactome
- Why is binding kinetics important in drug discovery?
- Binding kinetics impacts apparent and intrinsic potency measurements
- Apparent vs. intrinsic potency
- Fast vs. slow BK
- Slow and fast BK have different time courses of target engagement and disengagement
- Rebinding kinetics
- Time-dependent potency due to slow BK
- BK impacts potency measurement
- Binding kinetics impacts pharmacodynamics
- BK + PK = PD
- How can we incorporate BK in DD?
- Continuous in vitro assays for BK in DD
- Quenched or stopped flow
- Surface plasmon resonance
- Global progress curve analysis
- Radio or fluorescent ligand binding
- Jump dilution
- Cellular washout experiment
- Take home message
- Further reading
Topics Covered
- What is 'Binding Kinetics'
- The importance of binding kinetics in drug discovery
- Apparent vs. intrinsic potency
- Fast vs. slow binding kinetics
- Binding kinetics impacts pharmacodynamics
- Continuous in vitro assays for binding kinetics
- Practical guidance of binding kinetics
Links
Series:
Categories:
Talk Citation
Zhang, R. (2020, April 29). Binding kinetics in drug discovery [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 31, 2024, from https://doi.org/10.69645/DCCM9684.Export Citation (RIS)
Publication History
Financial Disclosures
- There are no commercial/financial matters to disclose.
A selection of talks on Pharmaceutical Sciences
Transcript
Please wait while the transcript is being prepared...
0:00
Hi, this is Rumin Zhang.
I'm going to lecture on binding kinetics in Drug Discovery.
I have been in drug industry for the last 28 years and counting.
For the last decade or so,
I have been keenly interested in the role of binding kinetics in drug discovery.
0:22
Today, I want to share with you
three important issues related to binding kinetics in drug discovery.
The what, why, and how questions.
First, what is binding kinetics?
Second, why is binding kinetics important in drug discovery?
Third, how can we practically incorporate binding kinetics in drug discovery?
0:46
What is binding kinetics?
Whenever we mention the word kinetics,
that connotes the dimension of time,
things that change with time is referred to as kinetics.
Binding kinetics is just one important aspect of kinetics,
which is all the time-dependent molecular events involving
binding interactions and conformational changes that comes with it.
In the lingo of binding kinetics,
life is a carefully choreographed symphony of binding kinetics.
Life is impossible without binding kinetics.
Drug discovery aims at normalizing any off-tune music notes in the symphony of life.
As a result, binding kinetics is intricately involved in drug discovery.
That's a very high level statement.
1:40
The simple case of binding kinetics is
a one-step bimolecular association and dissociation,
which are characterized by a second order association rate constant,
or k_on, in the unit of per molar concentration per unit time.
Also first-order dissociation rate constant, or called k_off,
in the unit of per unit time such as per second,
per minute, per hour.
Another important concept in binding kinetics is drug target residence time,
which is really the reciprocal of k_off,
the overall dissociation rate constant of the molecular binding event.
I'll come to that later if needed.
The simplest cases of binding kinetics is
unimolecular conformational change or isomerization,
characterized by first order rate constant like k_off.
Well known examples of binding kinetics includes
receptor and ligand binding and all downstream cascading events as a result.
Another example would be enzyme and substrate binding and subsequent substrate turnover.
The third example is transcriptional factors in the nucleus,
it's binding to activator or repressor molecules,
as well as the DNA target.
Yet a fourth example of binding kinetics is ion channel opening and closing.
Lastly, scaffolding protein partners binding to each other,
that will be also a popular example of binding kinetics.