QSAR modeling of globulin binding affinity of corticosteroids using AM1 calculations Kakali De, Chandana Sengupta and Kunal Roy * Drug Theoretics and Cheminformatics Lab, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Calcutta 700 032, India Received 4 March 2004; revised 24 March 2004; accepted 25 March 2004 Available online 6 May 2004 Abstract—A quantitative structure–activity analysis of binding affinity of a series of 30 steroids for corticosteroid-binding globulin was performed using Wang–Ford charges of the non-hydrogen common atoms obtained from molecular electrostatic potential surface of AM1 optimized energy-minimized geometries of the compounds. Attempts were made to include lipophilicity (log P ) and molar refractivity (MR) values of the whole molecules in the multivariate relations. The final relations were subjected to ‘leave-one- out’ cross-validation to check their predictive potential. It was found from the study that the charges of different atoms of the steroid nucleus [atoms 3, 4, 5 (ring A), 8, 9 (fusion points of rings B and C) and 16 (ring D)] contribute significantly to the binding affinity. This suggests the importance of these atoms/sites for the globulin binding affinity, which is also supported by previous reports on structure–activity relations of corticosteroids. Further, molar refractivity shows parabolic relation with the binding affinity, which indicates the possibility of dispersion interactions. The statistical qualities of the final equations generated in the present study (predicted variance 77–82%; explained variance 83–87%) are better than those of some of the previously reported models. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction The adrenal cortex secretes two major groups of steroids that have been arbitrarily classified as glucocorticoids and mineralocorticoids though carbohydrate metabo- lism is intimately linked to mineral balance in mam- mals. 1 The mineralocorticoids have effects on Na þ ,K þ and fluid balance while glucocorticoids have effects on carbohydrate, protein, fat and calcium metabolism, water excretion, cardiovascular system, skeletal muscle, central nervous system, lymphoid and blood cells, inflammatory and immunological phenomena. Anti- inflammatory and immunosuppressive actions of corti- costeroids, one of the major ‘pharmacological’ uses of this class of drugs, provide a protective mechanism in the physiological setting, since many of the immune mediators, which are associated with the inflammatory response, decrease vascular tone and could lead to cardiovascular collapse if unopposed by the adrenal corticosteroids. The pharmacological actions of cortico- steroids in different tissues and many of their physio- logical effects seem to be mediated by the same receptor. Thus, various corticoids used as pharmacological agents have side effects on physiological processes that parallel their therapeutic effectiveness. 2 Corticoid hormones exert their physiological actions by binding to recep- tors 3;4 that belong to a transcription factor superfamily, which also includes some of the proteins regulating steroid synthesis. Steroids stimulate sodium absorption by the activation and/or de novo synthesis of the ion- gated, amiloride-sensitive sodium channel in the apical membrane and that of Na þ /K þ -ATPase in the basolat- eral membrane. Corticosteroids exert anti-inflammatory action by a variety of mechanisms: (i) induction of lipocortins in macrophages leading to decreased pro- duction of prostaglandins, leukotrienes and platelet activating factor; (ii) negative regulation of genes for cytokines in macrophages, endothelial cells and lym- phocytes leading to decreased production of interleukins (IL-1, IL-2, IL-3, IL-6), tumour necrosis factor (TNF- a), etc.; (iii) decrease in products of acute phase reac- tants from macrophages leading to the interference in the complement functions; (iv) inhibition of immuno- globulin E (IgE) mediated histamine and leukotriene C4 (LTC 4 ) release from basophils, leading to interference in the antigen-antibody reaction; 5 etc. Keywords: QSAR; Corticosteroid-binding globulin; Modeling; AM1 calculations. * Corresponding author. Tel.: +91-33-2414-6676; fax: +91-33-2414-6677; e-mail: kunalroy_in@yahoo.com. URL: http://www.geocities.com/kunalroy_in 0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2004.03.055 Bioorganic & Medicinal Chemistry 12 (2004) 3323–3332