Binding kinetics in drug discovery

Published on April 29, 2020   49 min

Other Talks in the Series: Periodic Reports: Advances in Clinical Interventions and Research Platforms

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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.
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?
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.
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.