Conformational analysis and excited-state properties of a highly potent and totally selective aromatase inhibitor, 4, 4′-(1H-1, 2, 4-triazol-1-ylmethanediyl) dibenzo nitrile (letrozole)

Abstract

4, 4′-(1H-1, 2, 4-triazol-1-ylmethanediyl)dibenzonitrile (letrozole) is a highly potent and totally selective aromatase inhibitor used in treatment of early breast cancer in women who have experienced menopause (end of monthly menstrual periods) and who have had other treatments, such as radiation or surgery to remove the tumor. Conformational analysis studies of letrozole were based on Arguslab software. The molecular mechanics potential energy function wer evaluated in terms of energies associated with bonded interactions (bond length, bond angle and dihedral angle) as well as non-bonded interactions (Vander Waals and electrostatic). Surfaces were created to visualize excited state properties such as highest occupied molecular orbital's, lowest unoccupied molecular orbital's and electrostatic potential (ESP) mapped density. The steric energy for letrozole was calculated to be 0.116739 a.u. (73.255075 kcal/mol). The most energetically favourable conformation of letrozole was found to have a heat of formation of 1208.5864 kcal/mol. The self-consistent field (SCF) energy was calculated by geometry convergence function using RHF/AM1 method with a net charge of-1 and valence electron of 94, in ArgusLab software. The most feasible position for letrozole to act as a highly potent and totally selective aromatase inhibitor was found to be-116.271466 au (−72961.512600 kcal/mol)