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Molecular modeling of pilocarpine prodrugs: A theoretical investigation of pilocarpic acid esters
Author(s) -
Konschin Henrik,
Ekholm Michaela
Publication year - 1991
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560400724
Subject(s) - prodrug , molecular mechanics , pilocarpine , chemistry , protonation , molecular model , molecule , computational chemistry , hydrolysis , molecular dynamics , stereochemistry , combinatorial chemistry , organic chemistry , biochemistry , ion , neuroscience , epilepsy , biology
Pilocarpine is used as a topical miotic to control elevated intraocular pressure in the glaucoma‐afflicted eye. However, its ocular availability is low, it is subject to difficult delivery problems, and it is rapidly lost from the preferred site of action. Therefore, the prodrug approach has been used to design suitable pilocarpine derivatives. Possible pilocarpine prodrugs are pilocarpic acid esters of which little structural and molecular level information is available. Molecular modeling studies of a series of pilocarpic acid mono‐ and diester prodrugs have been done to gain an understanding of their general physicochemical properties. Molecular structures and conformers have been determined with molecular mechanics and quantum chemical AM 1 calculations. Both the molecular mechanics and the AM 1 methods yield similar molecular equilibrium structures. Calculations on the protonated forms of the molecules show that protonating introduces variations at the ester linkages prone to enzymatic attack. The calculations indicate, however, that spatial requirements may be more important than electrostatic characteristics for effective enzymatic hydrolysis of the pilocarpic acid diesters. Preliminary calculations on chosen examples of a new class of pilocarpine prodrugs of the bispilocarpic acid ester type are also reported.