Medium effects on the direct cis-trans photoisomerization of 1,4-diphenyl-1,3-butadiene in solution.

Quantum yields for the photoisomerization of trans,trans-1,4-diphenyl-1,3-butadiene (tt-DPB), determined in benzene, cyclohexane, methylcyclohexane, hexane, and perfluorohexane, confirm the low values reported earlier for benzene and cyclohexane and reveal even lower values in the last two solvents. In contrast to trans-stilbene (t-St), fluorescence and torsional relaxation leading to photoisomerization do not account exclusively for S(1)tt-DPB decay. Competing radiationless singlet excited-state decay pathways exist in tt-DPB, which do not lead to photoisomerization and may not involve large-amplitude torsional motions. Our results invalidate analyses of tt-DPB fluorescence quantum yields and lifetimes that assign all radiationless decay to the isomerization channel. Gas-phase chromatography analysis of tt-DPB photoisomerization in hexane shows the reaction to be concentration-independent and reveals, for the first time, a significant, two-bond photoisomerization pathway, φ(tt→tc) = 0.092 and φ(tt→cc) = 0.020. The dominant one-bond-twist (OBT) process is accompanied by a bicycle pedal (BP) process that accounts for almost 20% of tt-DPB photoisomerization. The OBT tt-DPB photoisomerization quantum yield is largest in benzene (Bz) and smallest in perfluorohexane (PFH). Contrary to expectations, reduction in medium friction in PFH is accompanied by a decrease in φ(tt→tc). The 1(1)B(u)/2(1)A(g) order and energy gap appear to control the contribution of torsional relaxation to radiationless decay. Lowering the 1(1)B(u) energy as in Bz favors photoisomerization. Reversal of the 1(1)B(u)/2(1)A(g) order in PFH is accompanied by short τ(f) and small φ(f) and φ(tt→tc) values that suggest the presence of competing 2(1)A(g) → 1(1)Ag relaxation paths that are unproductive with respect to photoisomerization. We conclude that the Birks extension to diphenylpolyenes of the Orlandi-Siebrand cis-trans photoisomerization mechanism is not valid. Photoisomerization appears to occur in the 1(I)B(u) state, and we argue that this applies to t-St as well.

Towards in silico lead optimization: scores from ensembles of protein/ligand conformations reliably correlate with biological activity.

Accurately ranking protein/ligand interactions and distinguishing subtle differences between homologous compounds in a virtual focused library in silico is essential in a structure-based drug discovery program. In order to establish a predictive model to design novel inhibitors of dihydrofolate reductase (DHFR) from the parasitic protozoa, Cryptosporidium hominis, we docked a series of 30 DHFR inhibitors with measured inhibition constants against the crystal structure of the protein. By including protein flexibility and averaging the energies of the 25 lowest protein/ligand conformers we obtained more accurate total nonbonded energies from which we calculated a predicted biological activity. The calculated and measured biological activities showed reliable correlations of 72.9%. Additionally, visual analysis of the ensemble of protein/ligand conformations revealed alternative ligand binding pockets in the active site. Using the same principles we then created a homology model of DHFR from Toxoplasma gondii and docked 11 inhibitors. A correlation of 50.2% between docking score and activity validates both the method and the model. The correlations presented here are particularly compelling considering the high structural similarity of the ligands and the fact that we have used structures derived from crystallographic data and homology modeling. These docking principles may be useful in any lead optimization study where accurate ranking of similar compounds is desired.