Premium
Research Article: Computer‐Assisted Design of Pro‐drugs for Antimalarial Atovaquone
Author(s) -
Karaman Rafik,
Hallak Hussein
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2010.01018.x
Subject(s) - density functional theory , atovaquone , chemistry , drug , linker , hydrogen bond , computational chemistry , ab initio , reaction rate , hydrogen , combinatorial chemistry , organic chemistry , computer science , molecule , pharmacology , plasmodium falciparum , medicine , catalysis , malaria , immunology , operating system
Density Functional Theory (DFT) and ab initio calculation results for the proton transfer reaction in Kirby’s enzyme models 1 ‐ 6 reveal that the reaction rate is largely dependent on the existence of a hydrogen bonding net in the reactants and the corresponding transition states. Further, the distance between the two reacting centers and the angle of the hydrogen bonding formed along the reaction path has profound effects on the rate. Hence, the study on the systems reported herein could provide a good basis for designing antimalarial (atovaquone) pro‐drug systems that can be used to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for pro‐drug 1Pro may be predicted to be about 10 11 times faster than that for a pro‐drug 4Pro and about 10 4 times faster than pro‐drug 2Pro: rate 1Pro > rate 2Pro > rate 4Pro . Thus, the rate by which the pro‐drug releases the antimalarial drug can be determined according to the nature of the linker (Kirby’s enzyme model 1 ‐ 6 ).