Correlation of LUMO* energies and free energies of binding for a series ofnifedipine analogues

A theoretical study was carried out in order to examine the potential of ph armacologically active 1,4-dihydropyridines (DHPs) to react via charge-tran sfer (CT) interactions with their binding site. For this purpose, the molec ular orbitals of nine mainly 3'-substituted DHP derivatives from the nifedi pine type were determined by semiempirical (AM1, PM3/tm, MNDO/d), ab initio (STO-3G, RHF 3-21G*, RHF 6-31G*) and electron density function (LSDA) meth ods. Qualitative analysis of the results revealed that for DHPs exerting hi gh affinity to the receptor site the energetically most favourable lowest u noccupied molecular orbital (LUMO) is found at the 4-phenyl ring, whereas t he highest occupied molecular orbital (HOMO) is detected at the DHP heteroc ycle. In contrast, DHPs with lower binding affinity produce only energetica lly less favourable unoccupied MOs at the 4-phenyl moiety (designated as LU MO*s) and in addition, also the HOMO is partially localized at this positio n. A quantitative approach performed by correlating experimentally estimate d free energies of binding and calculated LUMO* energies yielded satisfying correlations with correlation coefficients ranging from R = 0.80 (RHF 6-31 G**) to R = 0.91 (AM1). Based on these findings one can conclude that besid es the classical binding forces (electrostatic, hydrogen bonding, and van d er Waals interactions) also charge-transfer mechanisms should be involved i n DHP/binding site stabilization.