ANIONIC TETRAHEDRAL COMPLEXES AS SERINE-PROTEASE INHIBITORS

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 function al groups that may act as effective inhibitors. We relate this study t o serine proteases. We have analyzed all of the factors that operate i n 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 (Delt a Delta(MC-TC)) is the quantitative criterion that differentiates betw een the catalytic and inhibitory processes in proteases. The catalytic TC is shifted upwards (Delta Delta(MC-TC)>0) relative to the MC in th e free energy profile of the reaction, whereas the inhibitory tetrahed ral species is shifted downward (Delta Delta(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 o f an anionic TC for transition state analog inhibitors originates from the formation of a sigma-covalent bond between the reactive centers o f the enzyme and its inhibitor. This energetic effect is a quantitativ e 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 a greement is shown between modeled ab initio quantum chemical calculati ons and experimental results extracted from the literature.