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Structure-Based Fragment Screening Is Demonstrated To Be a Practical Lead Discovery Method for a Representative G‑ProteinCoupled Receptor Benjamin D. Stevens* Cambridge Laboratories, Pfizer Worldwide Research and Development, 620 Memorial Drive, Cambridge, Massachusetts 02139, United States
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ragment-based lead discovery efforts have made considerable impact on modern drug discovery programs over recent years.1 While less than a decade ago such approaches were limited in number and their promise was unknown, examples of such strategies leading to marketed therapeutics now exist.2 While in theory FBDD approaches can be utilized to screen for hits against membrane-bound targets, the practicality of such screening is inherently limited by a number factors (e.g., analytical methodology, operating window of functional assays).3 Indeed, fragment screening based against highly sensitive functional assays can exacerbate some of the more problematic aspects of this technique.4 Furthermore, as the most successful fragment-based programs often depend heavily on SBDD for lead optimization, the general lack of Xray structures for many GPCRs makes this a particularly challenging area. As of this time, there is little precedent for the combination of fragment and structure based approaches leading to the discovery of new GPCR ligands. In this recent issue of J. Med. Chem., Christopher et al. demonstrate the execution of a successful fragment-based screen and lead optimization that is driven completely by biophysical and in silico techniques.5 The authors selected the β1 adrenergic receptor for this effort, a quintessential class A aminergic GPCR for which numerous marketed drugs exist.6,7 An initial SPR screen was carried out utilizing 650 fragments against tethered β1 and A2A stabilized receptors (StaRs) (Figure 1). These “StaRs” are derived utilizing a GPCR stabilization technique recently advanced by Heptares. Several ligands with moderate affinity and selectivity for the β1 receptor were discovered. Of note was the phenylpiperazine class which is known for other adrenergic receptors but not for β1 (Figure 2).6,7 In silico docking of key fragments against known β1 ligands carazolol (inverse agonist) and carmoterol (agonist) along with several subsequent rounds of refinement
Figure 2. Key leads 19 and 20 discovered through the reported SBDD approach.
led to identification of optimized leads 19 and 20. Although the potency of these ligands is moderate (68 nM for 19 and 220 nM for 20), the ligand efficiency is outstanding, highlighting the key strength of such fragment-based lead optimization approaches (0.65 for 19 and 0.53 for 20). In one of the most exciting of the reported studies, X-ray structures of ligands 19 and 20 along with cyanopindolol (2) and carazolol (1) bound to the turkey β1 StaR were demonstrated. Analyses of the reported structures offer considerable evidence supporting the possibility of divergent pharmacology of ligands 19 and 20, most likely driven by the differences in the resulting conformation of the receptor serine 211. Unfortunately, the authors do not provide functional data supporting this interpretation and subsequent reports will be needed to confirm the unique pharmacology of these ligands. In this report, Christopher et al. have described a successful approach leading to the discovery of structurally novel β1
Figure 1. Screening paradigm used by Christopher et al.5 to discover novel ligands for the β1 adrenergic receptor. © XXXX American Chemical Society
Received: April 17, 2013
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dx.doi.org/10.1021/jm400561w | J. Med. Chem. XXXX, XXX, XXX−XXX
Journal of Medicinal Chemistry
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adrenoreceptor ligands driven exclusively by biophysical methods. This work highlights the promise of such technology for utilization in future GPCR lead discovery programs and provides an appealing alternative to traditional approaches for receptors where structural stabilization is possible.8 It will be particularly interesting to see how this approach fares in the context of orphan receptors or when seeking ligands with biased pharmacology.9
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AUTHOR INFORMATION
Corresponding Author
*Phone: 617-551-3542. E-mail: Benjamin.stevens@pfizer.com.
ABBREVIATIONS USED GPCR, G-protein-coupled receptor; FBDD, fragment-based drug discovery; SBDD, structure-based drug design; SPR, surface plasmon resonance; StaR, stabilized receptor
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REFERENCES
(1) Erlanson, D. A. Introduction to fragment-based drug discovery. Top. Curr. Chem. 2012, 317, 1−32. (2) Baker, M. Fragment-based lead discovery grows up. Nat. Rev. Drug Discovery 2013, 12, 5−7. (3) Erlanson, D. A.; McDowell, R. S.; O’Brien, T. Fragment-based drug discovery. J. Med. Chem. 2004, 47, 3463−3482. (4) Davis, B. J.; Erlanson, D. A. Learning from our mistakes: the “unknown knowns” in fragment screening. Bioorg. Med. Chem. Lett. 2013, DOI: 10.1016/j.bmcl.2013.03.028. (5) Christopher, J. A.; Brown, J.; Doré, A. S.; Errey, J. C.; Koglin, M.; Marshall, F. H.; Myszka, D. G.; Rich, R. L.; Tate, C. G.; Tehan, B.; Warne, T.; Congreve, M. Biophysical fragment screening of the β1adrenergic receptor: identification of high affinity arylpiperazine leads using structure-based drug design. J. Med. Chem. 2013, DOI: 10.1021/ jm400140q. (6) Westfall, T. C.; Westfall, D. P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems. In Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th ed.; Brunton, L., Ed.; McGraw Hill Medical: New York, 2011. (7) Westfall, T. C.; Westfall, D. P. Adrenergic Agonists and Antagonists. In Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th ed.; Brunton, L., Ed.; McGraw Hill Medical: New York, 2011. (8) Lundstrom, K. Present and future approaches to screening of Gprotein-coupled receptors. Future Med. Chem. 2013, 5, 523−538. (9) Kenakin, T.; Christopoulos, A. Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat. Rev. Drug Discovery 2013, 12, 205−216.
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