Current Computer Aided-Drug Design

Subhash C. Basak
Departments of Chemistry, Biochemistry & Molecular Biology University of Minnesota Duluth
Duluth, MN 55811


Computationally Designed Atovaquone Prodrugs Based on Bruices Enzyme Model

Author(s): Rafik Karaman, Beesan Fattash, Genarro Mecca and Maryam Bader

Affiliation: Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University, P.O. Box 20002, Jerusalem, Israel.


DFT molecular orbital calculations at B3LYP 6-31G (d,p) and B3LYP/311+G (d,p) levels and molecular mechanics (MM2) calculations of kinetic properties for Bruice’s systems 1-5 indicate that the rate enhancement in the cyclization of di-carboxylic semi-esters 1-5 is solely the result of strain effects and not proximity orientation ‘reactive rotamer effect”.

Furthermore, it was found that the activation energy in systems 1-5 and atovaquone ProD1- ProD5 is largely dependent on the difference in the strain energies of the tetrahedral intermediates and reactants, and no correlation was found between the cyclization rate and distance between the nucleophile and the electrophile (rGM).

Using the experimental t1/2 (the time needed for the conversion of 50% of the reactants to products) value for the cyclization reaction of di-carboxylic semi-ester 1 and the calculated log krel values for prodrugs ATQ ProD1- ProD5 the t1/2 values for the interconversion of ATQ ProD1- ProD5 to the parent drug were calculated. Thet1/2 values were: ATQ ProD3, 22.44 hours; ATQ ProD1, ATQ ProD2 and ATQ ProD4, few seconds and ATQ ProD5 few years. Therefore, the interconversion rate of atovaquone prodrugs to atovaquone can be programmed according to the nature of the prodrug linker.

Keywords: Antimalarial prodrugs, atovaquone prodrugs, Bruice’s rotamer effect, DFT calculations, Intramolecular hydrolysis, di-carboxylic semi-esters, bioavailability, strain energy.

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

Page: [15 - 27]
Pages: 13
DOI: 10.2174/15734099113096660049