THE ϕ, ψ SPACE OF BORON ISOSTERES OF AMINO ACIDS: ANAB INITIOSTUDY

Abstract

Boron isosteres [ CH3- CO - BH - CH(R) - CONHCH3; R = CH3, CH2OH , CH2SH ] of natural amino acids have been designed as inhibitors of serine protease based on boron's ability to mimic the transition state of the normal enzyme catalyzed reaction. The conformation and electronic properties of these isosteres have been determined by ab initio calculations at the HF/6-31G** level of theory. The global minimum energy structures of the boron isosteres (which are all identical) and the natural amino acids are radically different. Interestingly, the boron isosteres have favorable conformations with positive values for the ϕ dihedral, which are "disallowed states" for the natural amino acids. This is possible because of the smaller atomic size of boron compared to nitrogen. The molecular electrostatic potential of the boron isosteres is also very different from the natural amino acids. There is a positive potential around the boron atom, which provokes the attack of the Ser195– OH group in the enzyme, resulting in formation of an irreversible enzyme-inhibitor adduct.