Binding Kinetics & Residence Time – still an untapped opportunity for medicinal chemistry?                         

J Med Chem searches indicate binding kinetic studies are not being widely incorporated into medicinal chemistry strategies.

In 2006 Copeland and colleagues published a seminal paper describing the importance of binding kinetics in drug discovery strategy (Nature Rev Drug Discovery 2006 5, 730-739).  They discussed why equilibrium binding rate (K_i) often doesn’t provide a full understanding of compound potency.  They explained why association rate (k_a), dissociation rate (k_d) and target residence time (RT) are important considerations for attaining the desired in vivo potency and selectivity, along with more commonly discussed properties such as clearance and permeability.  At the time, few med chem efforts incorporated binding kinetics in their strategy and plans. Few projects had a stated goal for k_d or RT, and few were generating real time kinetics data to help guide medicinal chemistry design.

I saw Copeland paper as an important opportunity.  At the time I was leading a large group of scientists and technology experts working across a broad portfolio of projects at Pfizer’s Groton Labs.  Over the following years, and through numerous reorganizations, I expanded our biophysics and protein NMR expertise, focused them on a few high priority projects, and ensured they sought to proactively influence med chem design with kinetics data.  In the following year or so we saw strong indications of early success, and leads with longer residence time were identified in several projects.  We were well down the path of ensuring Copeland’s thesis was adopted across our local drug discovery community.

So fast-forward a bit…  I recently had the opportunity to meet with an energetic and insightful group of scientific leaders from Constellation Pharmaceuticals to discuss druggability and lead generation.  Together with 3 other industry and academic experts, we had a stimulating day discussing early drug discovery, including aspects of binding kinetics.  Coming off that enjoyable day I guess I had kinetics on my mind.  I asked myself – how aggressively are medicinal chemists across the industry adopting kinetics in medicinal chemistry?  My perception based on routine J Med Chem reading was not positive but I reckoned to look deeper. 

I searched J Med Chem from January 2007 to May 2010 (2868 research articles) using the following keywords – binding kinetics, residence time, dissociation rate, on rate and off rate.  I used various combinations and wildcards to ensure I was being inclusive.  This afforded a total of 128 unique hits.  I reviewed each one and excluded 85 that were not directly relevant to the question.*  I reexamined the remaining 43 papers and came to the following conclusions –

- 14 papers contained speculative statements suggesting binding kinetics may be a factor in their cellular or in vivo potencies but supporting data were not generated.   Examples include targeting DFG-out forms of kinases but without follow-up to confirm desired slow off rates.

- 24 papers generated kinetic data on optimized compounds and used these data to retrospectively explain potency.  These were not the type of prospective studies I was looking for but they do position the investigators for future efforts that optimize kinetics.

- 5 papers incorporated kinetics directly into their med chem strategies, generating real time data that influenced team decisions while their series was being optimized.  These are what I was looking for, and I list them below with a couple comments.  They are well worth a read.

Only 5 out of 2868!  It’s possible a few were missed, but I don’t think they would really change the interpretation.  Even if you consider all 43 papers as positive signs that kinetics are influencing drug discovery, the message is still clear to me.  So what do you think?  Do binding kinetics and residence still represent an untapped opportunity for medicinal chemistry?

Best regards, Ron Wester

Seabury BioScience Consulting LLC

www.seaburybioscience.com

rwester@seaburybioscience.com

860.303.0975

Individually, these 5 papers provide excellent examples of incorporating kinetics into medicinal chemistry.  Collectively, they show great diversity in their approach and perspective.  Enjoy!

1.     Pari Malherbe, et al. Journal of Medicinal Chemistry 2009 52 (22), 7103-7112.  Based on kinetics and modeling studies of NK3 antagonists against WT and mutated human and guinea pig receptors, a single ThràAla difference was proposed to explain one compound’s slow dissociation rate and apparent non-competitive binding behavior in GP.  The investigators then used this hypothesis to correctly predict binding characteristics for several new analogs in a 3^rd series.   This is where we need to get to – structural rationale for dissociation rate differences.

2.     Nicholas D. Adams, et al.
 Journal of Medicinal Chemistry 2010 53 (10), 3973-4001.  Slow on and off rates were found in a series of cell-potent Aurora B/C inhibitors.  Subsequent kinetics SAR studies indicated that a specific aryl substituent contributed to the long residence time.  The resulting development candidate’s long residence time was cited as a key differentiator from known clinical agents.  A great study, and no wonder – Bob Copeland is a co-author!

3.     Sang-Uk Kang, et al.  Journal of Medicinal Chemistry 2007 50 (8), 1978-1982.   SPR was used to track kinetics of Grb2 SH2 domain tripeptide antagonists and to demonstrate up to 10x differences in association and dissociation rates.  Different kinetics for groups of closely related analogs were made more apparent by plotting k_a vs k_d.  In my experience these plots are a really valuable way to visualize different balances of on/off rates within a series, often resulting in decisions to pursue leads with slower off rates in spite of weaker K_i’s.

4.     Linus S. Lin, et al. 
Journal of Medicinal Chemistry 2009 52 (11), 3449-3452.  Slower off rates and longer receptor residence times for peptidomimetic VLA-4 antagonists were prospectively targeted to help compensate for anticipated poor PK.  SAR of an alkylamino substituent led to the desired lower dissociation rates.  Adaptation of their primary bioassay (% bound @ 1 or 3 h) was a valuable resource-sparing approach to supporting med chem efforts in real time.

5.     Elisa Nuti, et al.
 Journal of Medicinal Chemistry 2009 52 (15), 4757-4773.  Based on kinetics profile of several new MMP-13 inhibitors the authors propose structural features responsible for slow dissociation rate.  While not a prospective SAR study per se, this work and their hypothesis positions them well for further improvements in potency through longer residence time.

*  Excluded hits were mostly of 2 types – those citing plasma or tissue residence time (n=49), and those focusing on the influence of allosteric modulators’ on agonist binding kinetics (10).  Both are important considerations for optimizing in vivo activity in their respective projects, but not the exact question I was asking.  Also excluded were several Perspectives and technical or methods studies.  These are important contributions in support of binding kinetics SAR studies but are not primary med chem SAR efforts.  The remaining exclusions had the search term only in a citation and did not discuss kinetics as part of their own study.