Jack Bikker

The medicinal chemistry community has become increasingly aware of the value of tracking calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. We hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose molecules to fail by steering discovery efforts toward achiral, aromatic compounds. We have proposed two simple and interpretable measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp(3) (Fsp(3)) where Fsp(3) = (number of sp(3) hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the molecule. We demonstrate that both complexity (as measured by Fsp(3)) and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs. In an attempt to explain these observations, we further demonstrate that saturation correlates with solubility, an experimental physical property important to success in the drug discovery setting.

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTKinase Domain Mutations in Cancer: Implications for Small Molecule Drug Design StrategiesJack A. Bikker*, Natasja Brooijmans, Allan Wissner, and Tarek S. MansourView Author Information Chemical Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965* To whom correspondence should be addressed. Telephone: 845 602 8819. Facsimile: 845 602 5682. E-mail: [email protected]Cite this: J. Med. Chem. 2009, 52, 6, 1493–1509Publication Date (Web):February 24, 2009Publication History Received22 August 2008Published online24 February 2009Published inissue 26 March 2009https://pubs.acs.org/doi/10.1021/jm8010542https://doi.org/10.1021/jm8010542review-articleACS PublicationsCopyright © 2009 American Chemical SocietyRequest reuse permissionsArticle Views7894Altmetric-Citations144LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Drug resistance,Genetics,Inhibitors,Monomers,Peptides and proteins Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTG-Protein Coupled Receptors: Models, Mutagenesis, and Drug DesignJack Andrew Bikker, Susanne Trumpp-Kallmeyer, and Christine HumbletView Author Information Parke-Davis Neuroscience Research Centre, Forvie Site, Robinson Way, Cambridge, United Kingdom CB2 2QB, and Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105 Cite this: J. Med. Chem. 1998, 41, 16, 2911–2927Publication Date (Web):July 30, 1998Publication History Received11 November 1997Published online30 July 1998Published inissue 1 July 1998https://pubs.acs.org/doi/10.1021/jm970767ahttps://doi.org/10.1021/jm970767areview-articleACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views934Altmetric-Citations95LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Agonists,Genetics,Ligands,Peptides and proteins,Receptors Get e-Alerts

Three-dimensional molecular models of the human melanocortin receptor (hMC1R) have been developed based upon the electron cryo-microscopic structure of bacteriorhodopsin and the electron density footprint of bovine rhodopsin. alpha-Melanocyte-stimulating hormone, Ac-Ser-Tyr-Ser-Met4-Glu-His-Phe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (alpha-MSH, alpha-melanotropin), and the superpotent, prolonged acting agonists, Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2 (NDP-MSH) and Ac-Nle4-c[Asp5-His6-DPhe7-Arg8-Trp9-Lys10]-NH2 (MTII), have been modeled into the proposed binding sites with specific ligand-receptor interactions identified. The melanotropin sidechain pharmacophores, DPhe7 and Trp9, are proposed to interact with a hydrophobic network of receptor aromatic residues in transmembrane regions 4, 5, 6, and 7. In addition, a hydrophilic network involving the ligand Arg8 and polar receptor residues located in transmembrane regions 2 and 3 were identified. Biological studies on alpha-MSH, NDP-MSH, MTII, and related peptides have been correlated with the proposed hMC1R model in terms of agonism, affinity, and prolongation. Finally, limited MC1R mutagenesis studies comparing alpha-MSH and NDP-MSH are interpreted within the context of the proposed hMC1R models.