3-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF ANGIOTESIN-CONVERTING ENZYME AND THERMOLYSIN INHIBITORS .2. A COMPARISON OF COMFA MODELS INCORPORATING MOLECULAR-ORBITAL FIELDS AND DESOLVATION FREE-ENERGIES BASED ON ACTIVE-ANALOG AND COMPLEMENTARY-RECEPTOR-FIELD ALIGNMENT RULES
Cl. Waller et Gr. Marshall, 3-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF ANGIOTESIN-CONVERTING ENZYME AND THERMOLYSIN INHIBITORS .2. A COMPARISON OF COMFA MODELS INCORPORATING MOLECULAR-ORBITAL FIELDS AND DESOLVATION FREE-ENERGIES BASED ON ACTIVE-ANALOG AND COMPLEMENTARY-RECEPTOR-FIELD ALIGNMENT RULES, Journal of medicinal chemistry, 36(16), 1993, pp. 2390-2403
The utility of comparative molecular field analysis (CoMFA), a three-d
imensional Quantitative Structure-Activity Relationship (3-D QSAR) par
adigm, as a tool to aid in the development of predictive models has be
en previously addressed (Depriest, S.D. et al., J. Am. Chem. Soc. 1993
, in press). Although predictive correlations were obtained for angiot
ensin-converting and thermolysin inhibitors, certain inadequacies of t
he CoMFA technique were noted. Primarily, CoMFA steric and electrostat
ic fields alone do not fully characterize the zinc-ligand interaction.
Previously, this was partially rectified by the inclusion of indicato
r variables into the QSAR table to designate the class of zinc-binding
ligand. Recent advances in molecular modeling technology have allowed
us to further address this limitation of the preceding study. Using m
olecular orbital fields derived from semiempirical calculations as add
itional descriptors in the QSAR table, predictive correlations were pr
oduced based on CoMFA and molecular orbital fields alone-indicator var
iables no longer being necessary. Arbitrary information concerning the
alignment of molecules under study within the active-site introduces
ambiguities into the CoMFA study. Crystallographic information detaili
ng the binding mode of several thermolysin enzyme inhibitors has previ
ously been used as a guide for the alignment of additional, noncrystal
lized, inhibitors. However, this process was complicated by the lack o
f parameters for zinc in the molecular mechanical force field. Therefo
re, zinc-ligand interactions were ignored during the standard minimiza
tion procedure. The use of field-fit minimization using complementary
receptor fields as templates is presented as a possible solution to th
e problem. Predictive correlations were obtained from analyses based o
n this method of molecular alignment. The availability of crystallogra
phic data for thermolysin enzyme-inhibitor complexes allowed for an al
ternate definition of the CoMFA region. Herein, promising results from
analyses using actual receptor active-site atom probe atoms are prese
nted.