Development of a quasi-dynamic pharmacophore model for anti-complement peptide analogues

Three quasi-dynamic pharmacophore models have been constructed for the complement inhibitor peptide compstatin, using first principles. Uniform sampling along 5-ns molecular dynamics trajectories provided dynamic conformers that are thought to represent the entire conformational space for nine training set molecules, compstatin, four active analogues, and four inactive analogues. The pharmacophore models were built using mixed physicochemical and structural properties of residues indispensable for structural stability and activity. Owing to the size and flexibility of compstatin, one-dimensional probability distributions of intrapharmacophore point distances, angles, and dihedral angles of different analogues spread over wide and overlapping ranges. More robust two-dimensional distance-angle probability distributions for two pharmacophore models discriminated individual analogues in terms of specific distance-angle pairs, but overall failed to identify the active and the inactive analogues as two distinct groups. Two-dimensional distance-dihedral angle probability distributions in a third pharmacophore model allowed discrimination of the groups of active and inactive analogues more effectively, with the highest-activity analogue having distinct behavior. The present study indicates that more stringent structural constraints should be used for a set of structurally similar but flexible peptides, as opposed to organic molecules, to convert dynamic conformers into pharmacophore models. Flexibility is a general aspect of the structure and function of peptides and should be taken into account in ligand-based pharmacophore design. However, the discrimination of activity using multidimensional probability surfaces depends on the peptide system, the selection of the training set, the molecular dynamics protocol, and the selection of the type and number of pharmacophore points.     

Semiempirical quantum chemical treatment of the standard reduction potentials of quinone and plastoquinone in water

The standard electrode potential for the quinone (Q)-hydroquinone (QH₂) couple in aqueous acidic media has been explicitly calculated. Molecular geometries of Q and QH₂ have been optimized. Protonation of Q, i.e., the formation of QH⁺ and QH, have been considered. Molecular geometries of these species have been thoroughly optimized. The energy of complexation of these molecules with water have been calculated by optimizing the structures of the hydrated complexes Q · 6H₂O, QH₂ · 6H₂O, QH⁺ · 6H₂O. and QH · 6H₂O. The ion–solvent interaction energy of QH⁺ · 6H₂O, in turn, has been calculated by considering the complex QH⁺ · 6H₂O…? 2H₂O, where the two extra water molecules approach the charge center of the complex QH⁺ · 6H₂O vertically from top and bottom of the quinonoid ring. The standard reduction potential calculated by the CNDO method, 0.8548 V, is somewhat larger than the experimental potential, 0.6998 V, at 25°C. But the INDO value, 0.7085 V, is in excellent agreement with the observed potential. The electrode potential for the plastoquinone (PQ)-plastohydroquinone (PQH₂) couple present in the aqueous pool in chloroplast has been calculated by the INDO method. The basic geometries of PQ, PQH⁺, and PQH_2/sb have been synthesized by adopting the optimized geometries of Q, QH⁺, and QH₂ and considering methyl substituents as well as an isoprenoid side chain containing up to 3 isoprene units with possible geometrical isomerism. The hydrated species PQ · 6H₂O, PQH⁺ · 6H₂O, and PQH₂ · 6H₂O are unstable compared to the isolated species PQ, PQH⁺, and PQH₂, respectively. In fact, we have found that the hydration of PQH⁺ and PQH₂ is much less extensive, and stability arises only when the hydroxyl groups in these two molecules are hydrogen-bonded to water molecules. But PQH⁺ is also stabilized through the association of two more water molecules in the vertical direction. For this reason, we have calculated the reduction potential of the PQ/PQH₂ system from the energies of the isolated molecules PQH₂ and the hydrated species PQH⁺ · 2H₂O. The computed standard reduction potential is 0.2785 V and it yields a potential of 0.07V at pH 7 at 25°C, which is in good agreement with the reduction potential 0.11 V observed for plastoquinone in the aqueous pool in chloroplast. © 1994 John Wiley & Sons, Inc.