Search PubMed⌕ Search

Biomedical subjects

A J Hopfinger

Publications and source records attributed to A J Hopfinger.

At least 37 records · Page 2Linked to original sources
PubMed1996

The rationale for E2020 as a potent acetylcholinesterase inhibitor.

The phase III drug-candidate, E2020, developed for treatment of Alzheimer's disease, and possibly other demenitas, and its analogues have been the focus of extensive molecular pharmacological and structural studies. The potency and selectivity of E2020 as an inhibitor of acetylcholinesterase, AChE, in the brain is established. A combination of molecular modeling and QSAR studies have been used throughout the evolution of the AChE inhibitor program leading to the benzylpiperidine series, and, ultimately, E2020. QSAR studies have identified requirements of optimize inhibition activity as a function of substituent choice on both the indanone and benzyl rings in the E2020 class of inhibitors. A combination of X-ray crystal structure studies of E2020 isomers and the molecular shape analysis, MSA, of E2020 and its analogues has led to a postulated active conformation, and molecular shape, for these AChE inhibitors. The active molecular shape corresponds to a high degree of shape similarity between the two E2020 isomers which, in turn, is consistent with the observed high inhibition potencies of both of these compounds. Intermolecular docking studies were carried out for E2020 and some analogues with the crystal structure of AChE when it became available. The docking simulations involving E2020 analogues suggest these inhibitors do not bind at the acetylcholine, ACh, active site, but rather at the most narrow location of the long channel leading to the active site. Intermolecular binding geometries are consistent with the postulated active conformations derived from structure-activity (receptor geometry independent) information.

Acetylcholinesterase↗
PubMed1996

Characterization of lipid membrane dynamics by simulation: 3. Probing molecular transport across the phospholipid bilayer.

PURPOSE: The goal of this study is to elucidate the role of the motions of the hydrocarbon chains of a phospholipid bilayer in penetrant diffusion. Penetrant size, as well as its position in the hydrocarbon core of the lipid bilayer, has also been explored regarding impact on the diffusion rate in a phospholipid bilayer. METHOD: Molecular dynamics, MD, simulations were carried out on a model dimyristoyl phosphatidylcholine (DMPC) membrane bilayer with and without methanol and propanol as penetrants. The MD trajectories were analyzed in terms of estimating time and space properties. RESULTS: These simulations show that torsion angle kink shifts in the hydrocarbon chains of phospholipids are natural occurrences in a bilayer assembly. The diffusion coefficients of methanol and propanol in a DMPC lipid bilayer, as calculated from the MD simulations, agree with experimental measurements. Both methanol and propanol show different diffusion rates in different regions of the hydrocarbon chain matrix of the lipid bilayer. Solute size has more impact on diffusion rate in the bilayer regions with high torsion angle order parameters, as compared to the regions with low torsion angle order parameters. CONCLUSIONS: The simulated transport behavior suggests that a kink shift diffusion mechanism is more likely to occur in regions with high torsion angle order parameters, and a free volume transport mechanism is more likely operative in the region with low torsion angle order parameters, mainly the center core of the bilayer. A three zone diffusion model is proposed for transport of a penetrant across a bilayer.

1-Propanol↗
PubMed1994

A generalized formalism of three-dimensional quantitative structure-property relationship analysis for flexible molecules using tensor representation.

A general formalism, based upon tensor representation of multidimensional data blocks, is presented to express relationships between dependent properties and independent molecular feature measures. The solutions to these data set problems are three-dimensional quantitative structure-property relationships, 3D-QSPRs. The molecular features are partitioned into the intrinsic molecular shape tensor, the molecular field tensor, a nonshape/field feature tensor, and an experimental feature tensor. The intrinsic molecular shape tensor contains information on the shape of a molecule within the contact surface while the molecular field tensor contains information outside of the contact surface. Molecular features not directly related to molecular shape are put into the nonshape/field tensor. Experimental measures not being used as dependent variables can be considered as independent molecular features in the experimental feature tensor. The 3D-QSPR is realized by constructing the transformation tensor which optimizes the statistical significance between the dependent and independent variables. Use of partial least squares (PLS) regression permits the unfolding of the composite feature tensor and the identification of the optimum transformation tensor. It is pointed out that a variety of fragment, whole-molecule, two-dimensional, and/or three-dimensional features can be placed into a nonshape/field tensor.

Models, Chemical↗
PubMed1994

Construction of a molecular shape analysis-three-dimensional quantitative structure-analysis relationship for an analog series of pyridobenzodiazepinone inhibitors of muscarinic 2 and 3 receptors.

A generalized three-dimensional (3D) quantitative structure-property relationship (QSPR) formalism, based upon molecular shape analysis (MSA), has been applied to an analog series of pyridobenzodiazepinone inhibitors of muscarinic 2 (M2) and 3 (M3) receptors. The fundamental goal of this application is to establish MSA-3D-QSARs (P = A = inhibition activity) that are based upon identifying the active conformations of these flexible analogs. The repetitive use of partial least squares (PLS) analysis permits the construction of the MSA-3D-QSARs. In addition to molecular shape, the identification of the properties of a lipophilic binding site and specific nonallowed steric receptor sites govern the MSA-3D-QSARs. The M2 and M3 QSARs suggest receptor subtype specificity might be realized by targeting upon a specific nonallowed steric receptor site. One conformation, common to both M2 and M3 receptors, emerges as dominant in the optimum MSA-3D-QSARs. However, other similar conformations are also found to yield meaningful MSA-3D-QSARs.

Animals↗
PubMed1994

Three-dimensional molecular shape analysis-quantitative structure-activity relationship of a series of cholecystokinin-A receptor antagonists.

The three-dimensional molecular shape analysis-quantitative structure-activity relationship (3D-MSA-QSAR) technique has been applied to develop correlations between the calculated physicochemical properties and the in vitro activities of a series of 3-(acylamino)-5-phenyl-2H-1,4-benzodiazepine cholecystokinin-A (CCK-A) antagonists. 3D-MSA-QSARs were developed for varying subsets of 53 analogs (J. Med. Chem. 1988, 31, 2235-2246). An active conformation is hypothesized for these compounds using the loss in biological activity-loss in conformational stability principle. After placing all compounds in the active conformation and performing pairwise molecular shape analysis, it was determined that not any one analog serves as the best shape reference compound. Nonidentical volumes of allowed receptor space are mapped out by different antagonists. A shape reference compound that consists of selected overlapped structures expands the definition of the accessible receptor space. This type of mutant improves the predicted activity of analogs over the value predicted if only one compound is chosen as the reference. Molecular shape, as represented by common overlap steric volume and nonoverlap steric volume, is the major factor contributing to the affinity of this class of compounds. Intramolecular conformational stability, as measured by the difference in energy of the active conformation and the global minimum energy conformation, is also important. It is further concluded from the 3D-MSA-QSAR models that part of the binding pocket for the 3-amido substituent has a preference for lipophilicity. The method used in this study of fragmenting the antagonist into spheres of varying radii and measuring lipophilicity isolates the substructure with highest probability of interacting with the receptor. Two indicator variables marking the presence of an N-methyl group and an o-fluoro atom on the 5'-phenyl substituent of the benzodiazepine ring structure also contribute significantly to the 3D-MSA-QSAR models. The 3D-MSA-QSAR results have led to the proposal of a 3D pharmacophore model for the benzodiazepine CCK-A antagonists.

Animals↗
PubMed1993

A model for the dynemicin-A cleavage of DNA using molecular dynamics simulation.

Molecular dynamics (MD) simulations to model possible reaction pathways of the dynemicin-A-DNA cleavage mechanism were performed. Two base-pairs sequences, ApCpTpApCpTp-3'/TpGpApTpGpAp-5' and CpApCpGpGpGp-3'/GpTpGpCpCpCp-5', were considered in the calculations. A model based on a prior study of intercalation of dynemicin-A and posterior activation of the drug was assumed in this study. The minimum energy minor groove intercalation complexes for dynemicin-A were used as starting structures in the MD simulations for the reactive intermediate species involved in the postulated action mechanism. The dynemicin-A diol derivative product of the opening of the epoxy ring was used as a "steric mimic" ligand for the DNA-reactive diaryl intermediate. The calculated changes in the geometry of the intercalation complex, due to the opening of the epoxy ring, correspond to the approach of the postulated intermolecular reaction centers in the intercalation states that are responsible for the highest observed DNA cleavage frequency observed. Conversely, unfavorable reaction geometries were found for the intercalation modes corresponding to the lowest observed DNA cutting frequencies.

Anthraquinones↗
PubMed1992

Eicosatetraynoic and arachidonic acid-induced changes in cell membrane fluidity consonant with differences in computer-aided design-structures.

ETYA (5,8,11,14-eicosatetraynoic acid), a competitive analogue of arachidonic acid (AA), inhibits the proliferation of U937 (human monoblastoid) and PC3 (human prostate) cancer cells, without the overt cytotoxicity associated with AA at similar concentrations. The mechanism of inhibition is not established. ETYA at 100 microM acutely increased whole cell and isolated microsomal membrane fluidity of both cell lines to a greater extent than arachidonic acid. PC3 cells incubated with ETYA for 72 h evidenced increased membrane fluidity. This was measured by the fluorescence polarization parameter, R, using the probes TMA-DPH and DPH for whole cell and isolated membrane fractions, respectively. Compared with whole cells, isolated membranes yielded a 10-20-fold increase in fluorescence intensity. The intramolecular conformational profiles of both ETYA and AA were explored using a combination of molecular mechanics energy minimization and molecular dynamics simulation. While it is possible that not all of the low energy conformational states of either molecule were sampled, the large number of low-energy conformers determined for ETYA correspond to kink deformed conformers relative to the family of AA conformers. These kinks make the molecular cross sections of ETYA larger than AA and arise from the four alkyne bond geometries. This structural finding is consistent with ETYA's greater effect on membrane fluidity. Dissociation between the extent of change in membrane fluidity due to ETYA or AA and inhibition of DNA synthesis can suggest that either (A) increased fluidity and inhibition of DNA synthesis are independent, or as we believe more likely, (B) greater membrane fluidity evoked by ETYA is important for inhibiting DNA synthesis, while changes induced by AA are insufficient or differ qualitatively from those required to initiate and sustain these nonlethal events.

Arachidonic Acids↗
PubMed1992

QSAR analyses of the substituted indanone and benzylpiperidine rings of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase.

QSAR analyses have been performed on the substituted indanone and benzylpiperidine ring substructures of a set of acetylcholinesterase, AChE, inhibitors of which 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride is a potent in vitro and ex vivo inhibitor. The method of molecular decomposition-recomposition was used to define the sets of molecular substructures and corresponding in vitro inhibition databases. A QSAR involving the magnitude of the dipole moment, the highest occupied molecular orbital (HOMO) energy, and a specific pi-orbital wave function coefficient of the substituted indanone ring substructure was constructed and found to be significant. The absence of any molecular-shape or bulk term in the QSAR, coupled with some of the relatively large substituents used to construct the QSAR, suggests considerable space is available around the indanone ring during the inhibition process. A set of QSARs were constructed and evaluated for substituents on the aromatic ring of the benzylpiperidine substructure. The most significant QSAR involves a representation of molecular shape, the largest principal moment of inertia, and the HOMO of the substituted aromatic ring. It appears that upon binding the receptor "wall" is closely fit around the benzyl ring, especially near the para position. Overall, the QSAR analysis suggests inhibition potency can be better enhanced by substitution on the indanone ring, as compared to the aromatic sites of the benzylpiperidine ring. Moreover, inhibition potency can be rapidly diminished, presumably through steric interactions with the receptor surface of AChE, by substitution of moderate to large groups on the benzyl ring, particularly at the para position.

Cholinesterase Inhibitors↗
PubMed1992

Conformational analyses and molecular-shape comparisons of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase.

Conformational analyses and molecular-shape comparisons were carried out on an analogue series of indanone-benzylpiperidine inhibitors of acetylcholinesterase (AChE). It was possible to define an active conformation with respect to the flexible geometry of the benzylpiperidine moiety, as well as an active conformation of the indanone ring-piperidine ring substructure for analogues having a single spacer group between these rings. No active conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine conformation could be postulated for analogues having two or three spacer units between the indanone and piperidine rings. Still, a receptor binding model can be constructed for all indanone and piperidine ring substructures. The postulated active conformation for 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride (1a), a potent AChE inhibitor, is close to the crystal structures of 1a with respect to the indanone-piperidine substructure, but differs from the crystal structures for the benzylpiperidine moiety. However, the crystal conformations and the postulated active conformation of the benzylpiperidine portion of the AChE inhibitor are estimated to be about equally stable. A trans-decalin analogue of 1a can adopt the postulated active conformation as shown by calculation and as seen in its crystal structure. The inactivity of this analogue is explained by the added steric size of the decalin unit and/or the time-average valence geometry behavior at the spiro junction to the indanone ring.

Cholinesterase Inhibitors↗
PubMed1992

Molecular dynamic simulations of the intercalation of benzothiopyranoindazole anticancer analogs with DNA models.

Fixed valence geometry intermolecular energy scans were carried out for a series of eight substituted anti-cancer benzothiopyranoindazoles (BTPI) interacting with (G-C) duplex models for DNA. The apparent intercalation energy minima identified in these scans were subsequently used as starting points in full-cartesian molecular dynamics relaxation simulations for 14 BTPIs. Intercalation in the major groove is preferred when both the ligand and DNA model possess formal charges. Otherwise, insertion of the ligand is modestly preferred from the minor groove. There are multiple minimum energy intercalation complexes within 5 kcal/mol of a global minimum for most analogs studied. The intercalation complex was investigated as a function of the molecular dielectric constant, epsilon, and the length of the (G-C) duplex segment. A wide range of epsilon values (3.5-50) can be employed without changing the relative order of stability of intercalation complexes. However, the absolute intercalation energy is quite sensitive to the selection of epsilon. (G-C)6 duplexes appear to be of adequate length to determine reliable estimates of the relative intercalation energetics.

Antineoplastic Agents↗
PubMed1992

QSAR analysis of a set of benzothiopyranoindazole anti-cancer analogs based upon their DNA intercalation properties as determined by molecular dynamics simulation.

The global low-energy intercalation thermodynamic properties for a set of 14 benzothiopyranoindazole (BTPI) analogs, determined by molecular dynamics (MD) simulation, were used as descriptors in a quantitative structure-activity relationship (QSAR) analysis to describe their observed anti-cancer activities. The calculated free-space binding (intercalation) energies by themselves, or in combination with ligand lipophilicity, do not yield significant QSARs. However, the free-space binding energy combined with the aqueous desolvation energy of the intercalation complex leads to a highly significant QSAR. The optimum QSAR corresponds to both the ligand and DNA model being charged, and a molecular dielectric of 40 used in the force field. The desolvation energy is computed using a hydration-shell model. The QSAR suggests that anti-cancer activity can be enhanced by increasing the intercalating free-space binding energy and/or decreasing the loss in the favorable hydration energies of both the ligand and DNA when intercalation occurs.

Antineoplastic Agents↗
PubMed1991

Conformational analysis and aqueous hydration studies of model peptides for the adhesive protein of the mussel, Mytilus edulis L.

Conformations of model peptides of the adhesive protein of the mussel, Mytilus edulis L were investigated using molecular mechanics. The protein structure was represented as the repeat of a 10-residue unit. This decamer, and di- and tri-decamers of it, were considered in the modeling. Incorporation of the unusual dopamine residue in the decamer repeat may be explained by its hydrogen bond forming ability via its 3-OH group to a proline carbonyl oxygen. This bond contributes to maintaining a double reverse beta-turn structure in the decamer. This conformation was found more stable than 3(1) and alpha helical conformations. Adjacent reverse beta-turn structures are connected by short segments (2 to 3 residues) having little conformational preference. Thus, the overall protein can possess a significant random nature, yet have a highly ordered embedded conformational component. Hydrophilic character is in line with the larger number of OH groups on the phenyl ring for residue 9 (the site of the Dopa residue). The dehydration free energy of the (3-OH)-Phe as compared to the Dopa derivative is less by 1.4 kcal per decamer unit. This amounts to more than 100 kcal energy gain in the dehydration process for the total protein.

Amino Acid Sequence↗
PubMed1991

Molecular mechanics and molecular dynamics studies of the intercalation of dynemicin-A with oligonucleotide models of DNA.

Intermolecular molecular modeling calculations to determine the intercalation behavior of dynemicin-A with DNA were performed using both static scanning and energy minimization and molecular dynamics relaxation techniques. Two base pair sequences, CpApCpGpGpGp-3'/GpTpGpCpCp-5' and ApCpTpApCpTp-3'/TpGpApTpGpAp-5', were considered in the calculations. The static scanning and energy minimization analyses identified multiple stable intercalation complexes for each base pair sequence. These complexes were subsequently used as starting structures in molecular dynamics relaxation simulations. Intercalation into the minor groove is preferred for both base pair sequences, and intercalation at a central CG site is preferred by about 9 kcal/mol over a TA site. However, intercalation at a TA site should be more reactive, in terms of chain scission, than that at a CG site, because dynemicin-A has more flexibility to achieve an intercalation geometry disposed to chemically react toward a base adjacent to the 3' side of a purine. This reaction model is consistent with experimental data.

Anthraquinones↗
PubMed1990

1-(substituted-benzyl)imidazole-2(3H)-thione inhibitors of dopamine beta-hydroxylase.

Molecular shape and quantitative structure-activity relationship (QSAR) analyses of 52 1-(substituted-benzyl)-imidazole-2(3H)-thione inhibitors of dopamine beta-hydroxylase were carried out. QSARs were developed for sets of 45 and sets of 47 analogues. Molecular shape, as represented by common overlap steric volume and the composite charge density on carbons 3, 4, and 5 of the substituted-benzyl ring are the major inhibition-potency descriptors. Five of the 52 compounds were eliminated prior to analyses on the basis of difficulties in characterizing shape and charge state. Two compounds were outliers. The active conformation deduced in the analyses is a low-energy conformer for both active and inactive inhibitors. This suggests that the intrinsic shape of the molecule due to the selection of X is more important than torsion-angle selection for the bonds between the two rings. The QSARs found in this study have only general similarities to one put forth by Kruse et al. using linear free energy descriptors.

Benzyl Compounds↗
PubMed1989

QSAR and molecular shape analysis of aryl-substituted alanine analogs as antigelling agents.

Quantitative structure activity relationship (QSAR) analyses have been performed to analyze the basis for the antigelling activity of a series of aryl-substituted alanine analogs, including both phenylalanine and tryptophan analogs. We find that these two groups of compounds should be treated separately, probably due to the difference in shape between the phenyl and indole rings in the respective side chains. For the phenylalanine analogs, the hydrophobicity of the side chain, as measured by the pi constants of the aromatic ring and their substituents, explains about 50% of the variance in antigelling activity. The square of the aromatic dipole moment and the steric overlap volume, as obtained from three dimensional molecular shape analysis, account for an additional 20% and 10% of the variance, respectively. For the tryptophan analogs, the majority of the variance is explained either by the square of the aromatic dipole moment (70%) or by the steric overlap volume (60%), with the two descriptors being highly correlated. This result suggests that the tryptophan analogs exhibit a relatively tight steric fit within their binding sites. The separate QSAR's of phenylalanine and tryptophan analogs also suggest that these two groups of compounds may bind to hemoglobin through different mechanisms or at different sites. For phenylalanine analogs, the hydrophobic interaction is dominant, and the dipole-dipole interaction and steric effects contribute to lesser extents. For the tryptophan analogs, the dipole-dipole interaction prevails with a high degree of steric shape complimentarity, but without any significant contribution from hydrophobic interactions. This information should assist in the future development of more specific and effective agents.

Alanine↗
PubMed1988

A molecular shape analysis and quantitative structure-activity relationship investigation of some triazine-antifolate inhibitors of Leishmania dihydrofolate reductase.

Molecular shape analysis (MSA) is used to develop quantitative structure-activity relationships (QSARs) for a set of 45 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-substituted-phenyl)-s-triazine inhibitors of Leishmania major dihydrofolate reductase (DHFR). The MSA-QSARs are equally significant to a QSAR developed by R. G. Booth et al. [1987) J. Med. Chem. 30, 1218) using linear free energy descriptors. However, the MSA-QSARs have the same general form as all other QSARs developed for DHFR inhibitors using MSA. Molecular shape, as represented by common overlap steric volume of each inhibitor with a shape reference standard triazine from the set of 45 compounds, and relative lipophilicity account for the large majority of the variance in inhibition potency as a function of substituent choice. A general method of evaluating the impact of different conformational states of flexible substituents upon the form and significance of MSA-QSARs is developed. The results of applying this method to the 45 triazines indicate that the MSA-QSARs are relatively independent of the type of conformation assigned to the large flexible substituents. It is important to note, however, that the types of substituent conformations used in this analysis cannot necessarily be related to an "active" substituent conformation.

Animals↗
PubMed1987

A quantitative structure-activity relationship analysis of some 4-aminodiphenyl sulfone antibacterial agents using linear free energy and molecular modeling methods.

A set of 36 congeneric 4-aminodiphenyl sulfones with measured inhibition potencies of dihydropteroate synthase were studied by using both linear free energy and molecular modeling methods. The goals of the investigation were to identify the "active" conformation for these compounds as inhibitors and, correspondingly, to contruct a quantitative structure-activity relationship (QSAR). These molecules are quite flexible and possess multiple conformational energy minima. Application of molecular shape analysis (MSA), using all intramolecular energy minima as part of the analysis, was not successful in generating a QSAR. However, the calculated intramolecular conformational entropy of these compounds was found to correlate with inhibition potency leading to a highly significant QSAR. Inhibition potency increases as entropy decreases. A decrease in entropy enhances the population of specific, symmetry-related minimum-energy conformations. In this indirect way, it was possible to postulate an "active" conformation. This investigation illustrates that specific knowledge of the "active" shape of a molecule may not provide the information needed to quantitatively explain the observed structure-activity relationship.

Anti-Bacterial Agents↗