COMPLETE THERMODYNAMIC DESCRIPTION OF H-BONDING IN THE FRAMEWORK OF MULTIPLICATIVE APPROACH

A complete thermodynamic description of H-bonding for drug design is proposed. The approach is based on applicability of multiplicative principle to enthalpy (DELTA-H) and free energy (DELTA-G) of complex formation by means of E(d)(E(a)) and C(d)(C(a)) factors: DELTA-H = 4.96 (kJ/mole)E(a)E(d) DELTA-G = 2.43 (kJ/mole)C(a)C(d) + 5.70 (kJ/mole), where E(d)(E(a)) and C(d)(C(a)) characterize the proton donor (acceptor) ability of compounds. The estimation of E and C values for 163 proton donors and 195 proton acceptors was done, making it possible to predict DELTA-H and DELTA-G for 31785 reactions. The comparison of these data with experimental ones for 936 reactions was carried out: DELTA-H(calc) = -0.27(+/- 0.45) + 1.00(+/- 0.02)DELTA-H(exp) n = 936 r = 0.954 s = 2.70 F = 9553 DELTA-G(calc) = -0.07(+/- 0.12) + 1.00(+/- 0.01)DELTA-G(exp) n = 936 r = 0.984 s = 1.11 F = 28556 The substituent effect on H-bonding ability of compounds was considered. It was established that varying of substituents at active sites can alter its proton donor (acceptor) properties over a wide range of E(d)(E(a)), C(d)(C(a)) with sufficient overlap between values of factors corresponding to different types of active sites. One could propose this approach to be applied to quantitative estimation of thermodynamic functions of H-bonding in substrate-receptor complexes, also for QSAR modelling, where E and C or its linear combination might be used as molecular descriptors characterizing quantitatively the relative H-bonding ability of biologically active compounds. The second type of applications is used by the authors when modelling QSAR by means of the program package CLARAS (Classification and Recognition of Active Structures).