THEO CHEM Journal of Molecular Structure (Theochem) 342 (1995) 161-171 Comparative QSAR study with electronic and steric parameters for CAMP derivatives with large substituents in positions 2, 6 and 8 S. Mureyan*,a, C. Bologab, M. Mracecb, A. Chiriacb, B. Jastorff, Z. Simond, G. Nk-ay-Szab6” zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQP “Technical University TimiJoara. Faculty of Indusrrial Chemistry, P-la Vicroriei No. 2, RO-1900 Timiqoara, Romania hUniwrsity Timiqoara, Faculty of Chemisrr?,, Str. Pesraloxi 16. RO-1900 TimiSoara, Romania ‘Department of Bioorganic Chemistry, University qf Bremen, D-2000 Bremen 33, German? ‘University af Medicine and Pharmacy. Department of Biophysics, Pta. _Eftimie Murgu 2. RO-1900 TimiSoara, Romania ‘Ehii.~ Universiry Budapest, Department of Theoretical Chemistr,v. H-1518 Budapest 112. PO Bou 32, Hungary , Received IO January 1995; accepted 4 February 1995 zyxwvutsrqponmlkjihgfedcbaZYXWVUT Abstract In order to discern structural characteristics for specific activation of four sites, AI and BI on cAK-I and AI1 and BII on cAK-II, an extended study on a series of CAMP derivatives with large substituents in positions 2, 6 and 8, has been performed. The effect of charged (at pH x 7) substituents upon the corresponding receptor affinities has also been investigated. The MTD method was used together with the estimated hydrophobicities of the base moiety and the charge on the substituent at the 6-(purinic)-position (calculated by the AMI method) as supplementary structural parameters. For the multiparametric correlations, r values between 0.73 and 0.98 were obtained, while in a cross- validation-like procedure, the Y& values are between 0.36 and 0.64. 1. Introduction CAMP, cyclic adenosine monophosphate, is a versatile key regulator of various cellular activities related to cell growth, differentiation, apoptosis, etc. Its derivatives are, therefore, of great potential interest for chemotherapy if one is able to find deri- vatives acting specifically only on one of the recep- tors involved [l]. Two general types (cAK-I and cAK-II) of CAMP-dependent protein kinases have been distinguished. The two isozymes have vir- tually identical catalytic subunits, but dissimilar regulatory subunits (RI and RII, respectively). * Corresponding author. The R subunits have a well-defined domain of structure which includes two different CAMP bind- ing sites: a kinetically stable site, termed Site B, and a kinetically labile Site A. These two sites exhibit different affinities for CAMP analogues [l]. No QSAR studies seem to have been performed for protein kinase activation of CAMP derivatives, but structure-activity relations were investigated by one of us by the so-called “testkit” approach [2]. Based on testkit approach results, in separate papers [3-51 we established QSARs by the Minimal Topological Difference (MTD) method for series of protein kinase activating CAMP derivatives in an attempt to discern structural characteristics for specific activation of the four sites: AI and BI on 0166-1280/95/$09.50 0 1995 Elsevier Science B.V. All rights reserved SSDI 0166-1280(95)04188-5