Computer assisted simulations and molecular graphics methods in molecular design. 1. Theory and applications to enzyme active-site directed drug design

On Transition Structures for Hydride Transfer Step: A Theoretical Study of the Reaction Catalyzed by Dihydrofolate Reductase Enzyme

“…The extrapolation of in vacuum studies of SPi-1 to discuss enzyme-catalyzed reactions raises important questions that have been addressed elsewhere (22)(23)(24)46). The analysis of the results presented in this work shows the existence of a minimal molecular model having a saddle point of index one which describes the essentials of the chemical interconversion step for a given enzyme mechanism, namely, main amplitudes in the TV, spatial arrangement of atoms and molecular fragments binded to the minimal model, bond distances, and angles of those atoms defining the minimal model.…”

“…Recently we have located the TSs for hydride transfer for models of different enzymes, liver alcohol dehydrogenase (17,18), formate dehydrogenase (19), lactate dehydrogenase (20), and DHFR, using a reduced molecular model (21). Furthermore, for the enzyme-catalyzed reactions studied so far (22), it is only the geometric arrangement of the SPi-1 in vacuum which can be docked at the active site of the corresponding enzyme.…”

“…The enzyme catalysis phenomena can be described as a specific binding process. The enzyme would have evolved to trap the reactants by molding them into a geometry reassembling, as much as possible, one of the SPi-1 in vacuum (22)(23)(24), and then a molecular deformation is introduced to adapt them at the corresponding active site surface. These results may be transposed to the DHFR reaction subject to the restrictions imposed by stereochemical considerations, so that a model emerges as a possibility for the chemical reduction step (25).…”

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

“…To satisfy this requirement, we must follow the one-step model, such as that proposed by Komiyama and Bender for amide bond cleavage reactions, rather than the generally accepted two-step model. [15][16][17][18][19][20][21][22][23] If we can find a candidate for a transition state that fits the bond cleavage reaction following the one-step model, it will then be plausible to design a single hapten that elicits antibodies catalyzing the amide bond cleavage reaction. Aided by computational chemistry, we propose …”

“…[15][16][17][18][19][20][21][22][23] X-ray analysis revealed that the triad structure of the active site, e.g. serine 195, histidine 57 and aspartic acid 109 in chymotrypsin, plays an important role in catalysis.…”