ISSN:
0948-5023
Keywords:
Protease
;
Methodology of inhibitor design
;
MO ab initio calculations
;
Free energy profile
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Potent inhibitors of proteases are constantly sought because of their potential as new therapeutic lead compounds. In this paper we report a simple computational methodology for obtaining new ideas for functional groups that may act as effective inhibitors. We relate this study to serine proteases. We have analyzed all of the factors that operate in the enzyme-substrate interactions and govern the free energy for the transformation of the Michaelis complex (MC) to the anionic covalent tetrahedral complex (TC). The free energy of this transformation ( ΔΔG MC-TC ) is the quantitative criterion that differentiates between the catalytic and inhibitory processes in proteases. The catalytic TC is shifted upwards (ΔΔG MC-TC 〉 0) relative to the MC in the free energy profile of the reaction, whereas the inhibitory tetrahedral species is shifted downward (ΔΔG MC-TC 〈 0). Therefore, the more stable the TC, the more effective it should be as an inhibitor. We conclude that the dominant contribution to the superstabilization of an anionic TC for transition state analog inhibitors originates from the formation of a σ-covalent bond between the reactive centers of the enzyme and its inhibitor. This energetic effect is a quantitative value obtained in ab initio calculations and provides an estimate as to whether a functional group is feasible as potent inhibitor or not. To support our methodology, we describe several examples where good agreement is shown between modeled ab initio quantum chemical calculations and experimental results extracted from the literature.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s0089460020390
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