Dihydrofolate distance geometry

GM Crippen. Quantitative structure-activity relationships by distance geometry Systematic analysis of dihydrofolate reductase inhibitors. I Med Chem 23 599-606, 1980. 

Crippen, G.M. (1980). Quantitative Structure-Activity Relationships by Distance Geometry Systematic Analysis of Dihydrofolate Reductase Inhibitors. J.Med.Chem.,23,599-606. 

Ghose, A.K. and Grippen, G.M. (1982) Quantitative structure-activity relationship by distance geometry quinazolines as dihydrofolate reductase inhibitors. J. Med. Chem., 25, 892-899. 

A. K. Ghose and G. M. Crippen, J. Med. Chem., 26, 996 (1983). Combined Distance Geometry Analysis of Dihydrofolate Reductase Inhibition by Quinazolines and Triazines. 

DHFR catalyzes the reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor (Fig. 17.1). Specifically, the pro-R hydride of NADPH is transferred stereospecifi-cally to the C6 of the pterin nucleus with concurrent protonation at the N5 position [1]. Structural studies of DHFR bound with substrates or substrate analogs have revealed the location and orientation of H2F, NADPH and the mechanistically important side chains [2]. Proper alignment of H2F and NADPH is crucial in enhancing the rate of the chemical step (hydride transfer). Ab initio, mixed quantum mechanical/molecular mechanical (QM/MM), and molecular dynamics computational studies have modeled the hydride transfer process and have deduced optimal geometries for the reaction [3-6]. The optimal C-C distance between the C4 of NADPH and C6 of H2F was calculated to be 2.7A [5, 6], which is significantly smaller than the initial distance of 3.34 A inferred from X-ray crystallography [2]. One proposed chemical mechanism involves a keto-enol tautomerization (Fig. 

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