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

Abstract

Boron isosteres [ CH 3- CO - BH - CH(R) - CONHCH 3; R = CH 3, CH 2 OH , CH 2 SH ] 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 Ser 195– OH group in the enzyme, resulting in formation of an irreversible enzyme-inhibitor adduct.

Geometry, transition states, and vibrational spectra of boron isostere of N‐methylacetamide by ab initio calculations

“…This means that a nucleophilic attack by, say, the serine hydoxyl group in serine proteases, would occur preferentially at the boron atom than at the carbonyl group. This precisely was the basis of our original design of boron peptides as potential inhibitors of serine protease, as reported in our previous work [11]. However, with "ESP-fitted charges," the difference in the partial positive charge of boron and the carbonyl carbon is slightly less.…”

“…This suggests that boron is actually "bonded" to four atoms rather than three, in the structures with ϭ 90°and 270°. The unique values of the angle (90°or 270°) assumed by boron peptides have a deep impact on the and angles that these peptides can adopt [11]. These differences can be used to design peptides with a specific stereochemistry and distinctive secondary structure.…”

“…We had reported for the first time the concept of boron isostere of amino acids (boron replacing nitrogen in the amide bond) as plausible serine protease inhibitors. The differences in the , space of N-acetyl-NЈ-methylamides of alanine, serine, and cysteine and their boron analogs (boron peptides) were explored at the HF/ 6-31G** level of theory [11].…”

Stationary Points on the PES of N-Methoxy Peptides and Their Boron Isosteres: An Ab Initio Study

“…In a subsequent paper, 15 we had studied hydroxy derivatives of boron (Figure 1, 2B) which are counterparts of the N-hydroxy derivatives of natural peptides (Figure 1, 2A). The acylhydroxyboranes (Figure 1, 2B) are more accessible synthetically than the acylboranes 13 (Figure 1, 1B) designed earlier.…”

Isosteres of peptides: boron analogs as dipolar forms of α‐amino acids – a theoretical study

“…7,8 We have reported in a series of papers the remarkable effects of the isosteric replacement of the C --O and N-H groups of peptides by boron, on the electronic properties, the geometry, and conformations of peptides. [9][10][11][12][13] The replacement of the N-H group by B-H causes a shift in the v torsion from 1808 in natural peptides to 908 in the boron isostere. It has been observed that modifying the B-H bond as B-OH and further as B-OCH 3 is able to induce a change in the conformation of the peptide backbone from a random coil-like state to a more ordered secondary structure.…”