Biomedical subjects
Publications and source records attributed to P P Mager.
The results of the backpropagation (BP) and generalized-regression genetic-neural (GRGN) network were compared using a series of nonpeptide arginine vasopressin VI antagonists. It was shown that both approaches are equivalent with respect to the recognition process while the BP network is superior over GRGN if the sample sizes are lowered by cross-validation.
The major protein constituent of the deposits of Alzheimer's disease is the so-called amyloid beta-peptide (Abeta) which was derived from proteolysis of a large transmembrane amyloid precursor protein. Some physicochemical and biological properties of the Abeta(1-42) peptide are described in this paper. Three functional areas of the soluble Abeta(1-42) peptide were found: (i) a lipophilic region in the middle of the peptide (Lys16 to Ala21), (ii) a second lipophilic core at the end (Lys28 to Val40), and (iii) polarized and charged, solvent-exposed areas. Using molecule coordinates found experimentally by NMR-solution spectroscopy, subsequent Gasteiger-MM+ geometry optimization led to the result that the first lipophilic core has an alpha-helical structure which is stabilized by intramolecular hydrogen-bonding forces. The result is a loop-like molecule. The second lipophilic core has a beta-sheet structure, and is able to form long-ranged, noncovalent, mainly hydrophobic forces with other beta-sheets of Abeta peptides. The beta-strands run in an antiparallel direction. The aggregates are highly stable and ordered. The negatively charged, solvent-exposed residues are potential sites for a crosslinking with membrane-bound receptors. A perspective in drug research is the development of drugs that bind to individual beta-sheets by noncovalent interactions, blocking the associations between the individual Abeta peptides and preventing the formation of amyloid aggregates.
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Conformations of manually built native and permethylated alpha-, beta-, and gamma-cyclodextrins (CD) were investigated using various computer assisted molecular modelling methods. Calculations were carried by applying the MM+ and the Tripos force field. The influences of atomic charges on the macrocyclic conformations during the optimization procedure were analyzed. The permethylation of hydroxyl groups of cyclodextrins changes bond and torsion angles between the glucose monomers and of the primary substituents. A method to determine the diameters of the cyclodextrin cavity by a modelling approach is described. It is shown that due to permethylation the larger cavity opening is increased and the primary substituents are canted outwards. As a consequence, the torus shape of the molecule changes, which is an important feature for docking and fitting studies.
A large, highly hydrophilic and constrained omega-loop was dissected from the allosteric area of HIV-1 reverse transcriptase (segment Tyr181 to Tyr188). The loop contains two amino acids (Asp185, Asp186) of the catalytic aspartyl triad (Asp110, Asp185, Asp186) and two amino acids (Tyr181, Tyr188) of the nonnucleoside RT inhibitor (NNRTI) binding sites. Hydrogen-bonding forces between the two folded peptide chains play the greatest role in holding the two chains together and in specifying the folding patterns. The treatment of solvents as dielectric continuums surrounding the AMBER force field model has shown changes in conformation but these changes were not dramatically because the omega-loop shape was completely maintained.
Using the molecular "cloud" of the HIV-1 reverse transcriptase (RT) as starting point, the peptide backbone of the polymerase subunit was visualized by molecular modelling. Then, the two subregions 98-106 and 179-190 of the allosteric area were "isolated". From the latter subregion, the Tyr181 to Tyr188 segment containing two amino acids (Asp185, Asp186) of the catalytic aspartyl triad and two amino acids (Tyr181, Tyr188) of the nonnucleoside RT inhibitor (NNRTI) binding sites, was excised. It was shown that the segment has a omega-like loop configuration which is highly hydrophilic. The two phenolic side chains of Tyr181 and Tyr188 represent the lipophilic "horizontal axes" of the omega-loop shape. The relative rigidity of the omega-loop is mainly based on a hydrogen bond between the peptide CO of Tyr181 and the peptide NH of Tyr188. Solvation in water increases the number of intramolecular hydrogen bonds. Therefore, desolvation is one of the conditions of binding with NNRTIs. Site-directed mutagenesis affects the hydrophilicity of the omega-loop while steric features are less influenced.
Although many physicochemical properties of chemically diverse nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) differ, there is a common three-dimensional feature. This shape is a rigid butterfly-like configuration which fits well into a sizable internal cavity of the allosteric area of the enzyme. The number of amino acids of the allosteric receptor sites that contribute to NNRTIs binding correlates with the degree of the butterfly-like shape. It seems that molecular rigidity of the butterfly-like shape, the drug affinity and the probability of resistance development are closely related.
Regarding theophylline as representative xanthine derivative, it was shown that the net charges of various semiempirical quantum chemistry methods are transferable by scaling. PM3 should be preferred for calculation of xanthine derivatives. Molecular modelling indicated that there is a conformational similarity of the lead structure of xanthine and adenosine derivatives. The substituents bound to the C8 of xanthine and to the C2 of adenosine derivatives are involved in the discrimination into adenosine A2 antagonists and agonists. The A2 affinity of xanthines is mainly determined by the type of N7 substitution (hydrogen/methyl), the lipophilic substituent constant related to the C8 substituents, and the dipole moment of the molecules. To simulate chemically the A1 affinity, a further term (lowest unoccupied molecular orbital energy) must be added. In addition, hydrogen-bonding forces were hypothesized using a newly synthesized 3,6-diaminocarbazole derivative as synthetic adenosine pseudoreceptor.
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Multivariate quantitative conformation-activity relationships of a series of 4-amino-2-carboxytetrahydroquinolines have shown that the biological activity profile (inhibition of (3H)glycine binding to rat cortical membranes and antagonism of depolarizations due to N-methyl-D-aspartic acid (NMDA) in a rat cortical slice preparation) depends on the molar refraction of the substituents, the total energy related to the nitrogen atom and the carbon atom of the -NHCOR1 bridge of the lead molecule (Figure 1), and the 1.4 nonvalency energy. Diagnostic statistics shows that the model assumptions are approximately satisfied.
The isoenzyme protein kinase C (PKC) inhibitory activity of substituted bisindolylmaleimides depends on the molecular weight, the total charge, and dipole moments. The validity of the resulting QSAR equation was investigated by interactive diagnostic statistics and multivariate simultaneous statistical inference. Molecular mechanics and dynamics can be used to study possible reasons of flagged observations (high-leverage points, influential data, outliers) of QSAR systems.
A profile of antimuscarinic response and its duration of action of substituted 7-amino-1-hydroxy-5-heptyn-2-ones can be correlated against the molecular space, partial energy of the nitrogen atom of the side chain, and the STERIMOL parameters maximum width and length. The molecules are conformationally rigid in the low-energy state which seems to be condition for specific interactions with accessory binding sites of the muscarinic M3 receptor. The agents can be activated energetically to more flexible compounds which may favor covalent binding to the catalytic center of the M3 receptor. On the basis of the results obtained, a common pharmacophore of three structurally diverse classes of M3 antagonists is proposed. The matrix of optimized Cartesian coordinates of a molecule can be transformed to a vector-valued observation which can be applied to develop quantitative conformation-activity relationships.
Quantitative structure-activity relationships of antiallergic N-[4-[4-(diphenylmethyl)-1-piperazinyl]-butyl]-3-(3-pyridyl)acr yl-amide s were studied. It was shown that the biological action depends on lipophilic and steric substituent features; apolar but small groups improve activity. Diagnostic statistics indicated that the QSAR equation is relatively robust. It was hypothesized from molecular modelling that the substituents influence primarily the pharmacokinetic-toxokinetic behavior of the compounds.
Quantitative structure-activity relationships of a series of substituted 1,4-dihydropyridine calcium channel antagonists were studied. The analysis is difficult because of the problem of multicollinearity of substituent parameters, a high-leverage point, and position-dependent grouped observations. Canonical regression appears to be the method of choice. With respect to a maximum activity, it was shown that the following rank order of substituent parameters exists: Lipophilicity approximately ortho-position > inductivity > minimum width > meta-position. The molecular conformation of antagonists does not differ markedly (with exception of nifedipine derivatives and nimodipine), but differences seem to exist between the antagonists and the activator BAY K 8644.
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