Ab initio study toward designing transition-state analogues which elicit proteolytic catalytic antibodies

New haptens useful for eliciting proteolytic antibodies are proposed. Trans ition state conformations of the amide and ester bond cleavages of simple q uantum models were obtained by HF/6-31G* ab initio calculations. The result s suggested that in our model of the transition state, forming the tetrahed ral structure at the carbonyl carbon in a nucleophilic addition step is suf ficient for ester bond cleavage, while formation of both the tetrahedral st ructure and the appropriate orientation of the lone-pair electrons on the n itrogen for the proton addition is necessary for amide bond cleavage. The k ey feature for designing good and/or potent haptens deduced from the transi tion state model could therefore be that both the tetrahedral conformation at the carbonyl carbon and proper orientation of lone pairs are simultaneou sly and appropriately reproduced in the haptens. Based on calculations, we designed potentially appropriate new haptens with the phosphonamidate funct ional group for eliciting proteolytic antibodies. Copyright (C) 2000 John W iley & Sons, Ltd.