Proteochemometric Mapping of the Interaction of Organic Compounds with Melanocortin Receptor Subtypes

Abstract

Proteochemometrics was applied in the analysis of the binding of organic compounds to wild-type and chimeric melanocortin receptors. Thirteen chimeric melanocortin receptors were designed based on statistical molecular design; each chimera contained parts from three of the MC 1,3-5 receptors. The binding affinities of 18 compounds were determined for these chimeric melanocortin receptors and the four wild-type melanocortin receptors. The data for 14 of these compounds were correlated to the physicochemical and structural descriptors of compounds, binary descriptors of receptor sequences, and cross-terms derived from ligand and receptor descriptors to obtain a proteochemometric model (correlation was performed using partial least-squares projections to latent structures; PLS). A well fitted mathematical model (R 2 ϭ 0.92) with high predictive ability (Q 2 ϭ 0.79) was obtained. In a further validation of the model, the predictive ability for ligands (Q 2 lig ϭ 0.68) and receptors (Q 2 rec ϭ 0.76) was estimated. The model was moreover validated by external prediction by using the data for the four additional compounds that had not at all been included in the proteochemometric model; the analysis yielded a Q 2 ext ϭ 0.73. An interpretation of the results using PLS coefficients revealed the influence of particular properties of organic compounds on their affinity to melanocortin receptors. Threedimensional models of melanocortin receptors were also created, and physicochemical properties of the amino acids inside the receptors' transmembrane cavity were correlated to the PLS modeling results. The importance of particular amino acids for selective binding of organic compounds was estimated and used to outline the ligand recognition site in the melanocortin receptors.Melanocortin receptors (MCRs) are members of the seven transmembrane (TM)-spanning G protein-coupled receptor (GPCR) superfamily. To date, five MCR subtypes, MC 1-5, are recognized in mammals, and each of these subtypes stimulates cAMP signal transduction pathways. An endogenous group of peptides, the melanocyte-stimulating hormones (MSH) and corticotropin and agouti and agouti-related protein, bind to the MCRs with agonistic and antagonistic properties, respectively. However, an exception is the MC 2 R, which binds only the corticotropin (Schioth et al., 1996a).The MCRs have a wide range of physiological roles. The MC 1 R regulates melanin pigment formation in the skin and has a regulating role in the immune system. The MC 2 R regulates corticosteroid production of the adrenals. The MC 3 and MC 4 Rs play important roles in controlling feeding and sexual behaviors, and the MC 5 R is involved in the regulation of exocrine glands (Wikberg et al., 2000Wikberg, 2001). The potential of using the MCRs as targets for drugs to treat important medical conditions such as obesity/diabetes, inflammatory conditions, and sexual dysfunctions prompts the need for compounds that show high specificity for particular MCR subtypes. However, the design of selective dru...

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