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PubMed1992

Relationship of three-dimensional structure of muscarinic antagonists to antimuscarinic activity: structure of thiodeacylaprophen hydrochloride.

C20H28NS+.Cl-, 2-(diethylamino)ethyl 1,1-diphenylethyl sulfide hydrochloride (thiodeacylaprophen hydrochloride), M(r) = 349.9, orthorhombic, P2(1)2(1)2(1), a = 8.933 (2), b = 11.710 (3), c = 18.934 (4) A, V = 1980.6 (7) A3, Z = 4, Dx = 1.173 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 26.70 cm-1, F(000) = 752, room temperature, final R = 4.1% for 1417 reflections with /Fo/ greater than 3 sigma (F). Thiodeacylaprophen crystallized as a tertiary amine hydrochloride salt. The S--C--C--N+ segment adopts a trans configuration as does one of the Cphenyl--C--S--C segments. A comparison of the structure of thiodeacylaprophen with the crystal structures of potent antimuscarinic agents suggests that the relatively weak antimuscarinic activity of thiodeacylaprophen compared to atropine and aprophen may be substantially due to the short intramolecular S...N+ distance of 4.106 (6) A. Other contributing structural factors may include the direction of the N+--H bond and restricted accessibility of the sulfur atom for interatomic interactions.

Animals↗
PubMed2001

Structure determination of human and murine beta-defensins reveals structural conservation in the absence of significant sequence similarity.

Defensins are cationic and cysteine-rich peptides that play a crucial role in the host defense against microorganisms of many organisms by their capability to permeabilize bacterial membranes. The low sequence similarity among the members of the large mammalian beta-defensin family suggests that their antimicrobial activity is largely independent of their primary structure. To investigate to what extent these defensins share a similar fold, the structures of the two human beta-defensins, hBD-1 and hBD-2, as well as those of two novel murine defensins, termed mBD-7 and mBD-8, were determined by nuclear magnetic resonance spectroscopy. All four defensins investigated share a striking similarity on the level of secondary and tertiary structure including the lack of a distinct hydrophobic core, suggesting that the fold is mainly stabilized by the presence of three disulfide bonds. In addition to the overall shape of the molecules, the ratio of solvent-exposed polar and hydrophobic side chains is also very similar among the four defensins investigated. It is significant that beta-defensins do not exhibit a common pattern of charged and hydrophobic residues on the protein surface and that the beta-defensin-specific fold appears to accommodate a wide range of different amino acids at most sequence positions. In addition to the implications for the mode of biological defensin actions, these findings are of particular interest because beta-defensins have been suggested as lead compounds for the development of novel peptide antibiotics for the therapy of infectious diseases.

Amino Acid Sequence↗
PubMed2002

RGS12TS-S localizes at nuclear matrix-associated subnuclear structures and represses transcription: structural requirements for subnuclear targeting and transcriptional repression.

RGS12TS-S, an 1,157-amino-acid RGS protein (regulator of G protein signaling), is a nuclear protein that exhibits a unique pattern of subnuclear organization into nuclear foci or dots when expressed endogenously or ectopically. We now report that RGS12TS-S is a nuclear matrix protein and identify structural determinants that target this protein to the nuclear matrix and to discrete subnuclear sites. We also determine the relationship between RGS12TS-S-decorated nuclear dots and known subnuclear domains involved in control of gene expression and provide the first evidence that RGS12TS-S is functionally involved in the regulation of transcription and cell cycle events. A novel nuclear matrix-targeting sequence was identified that is distinct from a second novel motif needed for targeting RGS12TS-S to nuclear dots. RGS12TS-S nuclear dots were distinct from Cajal bodies, SC-35 domains, promyelocytic leukemia protein nuclear bodies, Polycomb group domains, and DNA replication sites. However, RGS12TS-S inhibited S-phase DNA synthesis in various tumor cell lines independently of Rb and p53 proteins, and its prolonged expression promoted formation of multinucleated cells. Expression of RGS12TS-S dramatically reduced bromo-UTP incorporation into sites of transcription. RGS12TS-S, when tethered to a Gal4 DNA binding domain, dramatically inhibited basal transcription from a Gal4-E1b TATA promoter in a histone deacetylase-independent manner. Structural analysis revealed a role for the unique N-terminal domain of RGS12TS-S in its transcriptional repressor and cell cycle-regulating activities and showed that the RGS domain was dispensable for these functions. These results provide novel insights into the structure and function of RGS12TS-S in the nucleus and demonstrate that RGS12TS-S possesses biological activities distinct from those of other members of the RGS protein family.

Animals↗
PubMed2006

Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding.

To search for endogenous estrogens that may have preferential binding affinity for human estrogen receptor (ER) alpha or beta subtype and also to gain insights into the structural determinants favoring differential subtype binding, we studied the binding affinities of 74 natural or synthetic estrogens, including more than 50 steroidal analogs of estradiol-17beta (E2) and estrone (E1) for human ER alpha and ER beta. Many of the endogenous estrogen metabolites retained varying degrees of similar binding affinity for ER alpha and ER beta, but some of them retained differential binding affinity for the two subtypes. For instance, several of the D-ring metabolites, such as 16 alpha-hydroxyestradiol (estriol), 16 beta-hydroxyestradiol-17 alpha, and 16-ketoestrone, had distinct preferential binding affinity for human ER beta over ER alpha (difference up to 18-fold). Notably, although E2 has nearly the highest and equal binding affinity for ER alpha and ER beta, E1 and 2-hydroxyestrone (two quantitatively predominant endogenous estrogens in nonpregnant woman) have preferential binding affinity for ER alpha over ER beta, whereas 16 alpha-hydroxyestradiol (estriol) and other D-ring metabolites (quantitatively predominant endogenous estrogens formed during pregnancy) have preferential binding affinity for ER beta over ER alpha. Hence, facile metabolic conversion of parent hormone E2 to various metabolites under different physiological conditions may serve unique functions by providing differential activation of the ER alpha or ER beta signaling system. Lastly, our computational three-dimensional quantitative structure-activity relationship/comparative molecular field analysis of 47 steroidal estrogen analogs for human ER alpha and ER beta yielded useful information on the structural features that determine the preferential activation of the ER alpha and ER beta subtypes, which may aid in the rational design of selective ligands for each human ER subtype.

Diethylstilbestrol↗
PubMed1994

Nisamycin, a new manumycin group antibiotic from Streptomyces sp. K106. II. Structure determination and structure-activity relationships.

Nisamycin, a novel manumycin group antibiotic, was isolated from the culture broth of Streptomyces sp. K106. Structural elucidation of nisamycin was achieved by detailed NMR spectral analyses and comparison of the NMR data of nisamycin with those of other manumycin group antibiotics. The structure was confirmed by chromic acid oxidation. The absolute stereochemistry of nisamycin was determined to be 4R, 5S and 6R from the CD spectra of nisamycin and chromic oxidation of nisamycin. In addition, some structure activity-relationships were examined.

Anti-Bacterial Agents↗
PubMed2000

Constraint-based assembly of tertiary protein structures from secondary structure elements.

A challenge in computational protein folding is to assemble secondary structure elements-helices and strands-into well-packed tertiary structures. Particularly difficult is the formation of beta-sheets from strands, because they involve large conformational searches at the same time as precise packing and hydrogen bonding. Here we describe a method, called Geocore-2, that (1) grows chains one monomer or secondary structure at a time, then (2) disconnects the loops and performs a fast rigid-body docking step to achieve canonical packings, then (3) in the case of intrasheet strand packing, adjusts the side-chain rotamers; and finally (4) reattaches loops. Computational efficiency is enhanced by using a branch-and-bound search in which pruning rules aim to achieve a hydrophobic core and satisfactory hydrogen bonding patterns. We show that the pruning rules reduce computational time by 10(3)- to 10(5)-fold, and that this strategy is computationally practical at least for molecules up to about 100 amino acids long.

Algorithms↗
PubMed1992

Structure-activity study and design of multidrug-resistant reversal compounds by a computer automated structure evaluation methodology.

We have studied the relation between the structure and the multidrug resistance-reversal activity of a set of diverse chemicals with the MULTICASE structure-activity program. A number of key structural features were identified as being related to multidrug resistance reversal activity. Using these key features, we identified seven new compounds predicted to have substantial activity. These were obtained and tested experimentally on a CHO/CHRC5 cell line derived from the AB1 Chinese hamster ovary line in the presence of vincristine and vinblastine. Of the seven compounds tested so far, four showed substantial reversal activity, the most potent of them exhibiting activity at par with verapamil.

Animals↗
PubMed1989

Structure-activity relationship between prostacyclin and its platelet receptor. Correlation of structure change and the platelet activity.

Correlation analysis between the structural changes of PGI2 and the corresponding changes in platelet activity was performed to look into the following structural features: (1) the spatial relationship of critical functional groups, (2) conformational flexibility of the molecule as a result of chemical modification; (3) charge distribution around C6a; (4) hydrogen-bonding capability and mispairing and (5) the steric effects which resulted from chemical modifications. Our studies led to three important conclusions: (1) The C1 carboxylate and C11, C15 hydroxyl groups of PGI2 are essential for platelet activity. Modifications that change their relative positions reduce the activity. The ring structure and the C5 and C13 double bonds are molecular designs to maintain this unique geometry. (2) The C6a oxygen, although not vital to the binding geometry, is important for the biological potency. Decreasing the electronegativity of C6a oxygen leads to decreased potency. (3) We propose that any additional hydrogen-bond donor present between C1 and C15 could cause a hydrogen-bond mispairing and therefore a decreased activity. These findings should be useful for designing new PGI2 analogues and for determining the configuration of receptor-associated PGI2 by a molecular mechanics technique.

Animals↗
PubMed1995

Primary structure, sequence-specific 1H-NMR assignments and secondary structure in solution of bromelain inhibitor VI from pineapple stem.

One of the bromelain inhibitors, isoinhibitor VI (BI-VI), was purified from pineapple stem powder and its complete amino acid sequence was determined by conventional protein sequencing. These results revealed that the protein consists of an 11-residue light chain and a 41-residue heavy chain, cross-linked to each other by disulfide bonds to form the native inhibitor of 52 residues (M(r) = 5888). The secondary structure of BI-VI was analyzed based on the sequence-specific 1H resonance assignment of its two-dimensional NMR spectra. BI-VI was shown to be composed of two domains (A and B) which are formed by antiparallel beta-sheets, but has no alpha-helix. These results were consistent with the CD spectra of BI-VI. Residues Lys27-Ile29 (heavy chain) form a triple-stranded antiparallel beta-sheet with residues Asp9-Tyr11 and Lys22-Glu24 (heavy chain) in the A domain and residues Cys5-Cys7 (heavy chain) form another triple-stranded beta-sheet with residues Cys6-Cys8 (light chain) and Asp32-Ile34 (heavy chain) in the B domain. The secondary structure as well as the primary structure of BI-VI was distinctly different from that of the other cysteine protease inhibitor, cystatin, and from that of basic pancreatic trypsin inhibitor.

Amino Acid Sequence↗
PubMed1993

[The studies on electronic structure and structure-activity relationships of [Leu5]-enkephalin].

The quantum chemical (INDO) calculations have been undertaken for [Leu5]-enkephalin. The electronic structure was investigated, the active site, the way of action and structure-activity relationship were discussed. It was found that the region of N(1) is the main active site for acceptance of electron, the region of O(51) and O(52) is the main active site for providing electron when interacting with the opiate receptor. [Leu5]-enkephalin was compared with morphine and R31833 in electronic and spatial structure of active site. Study of the results showed that the N(1) in [Leu5]-enkephalin corresponds to the N in morphine and the N(9) in R31833, phenyl of Tyr1 in [Leu5]-enkephalin corresponds to the phenyl in morphine and the phenyl of phenylethyl in R31833, the O(51) and O(52) in [Leu5]-enkephalin corresponds to the O(3) in morphine and the O(25) in R31833, the O(4) in [Leu5]-enkephalin corresponds to the O(29) or O(27) in R31833. On the basis of these studies, it was inferred that these compounds have common feature in pharmacophore. They not only have the same way of action but also have common site of action in the receptor when they interact with the opiate receptor.

Analgesics, Opioid↗
PubMed1994

Structure and function in rhodopsin. Requirements of a specific structure for the intradiscal domain.

We concluded previously from mutagenesis in the intradiscal domain of bovine rhodopsin that the formation of a tertiary structure comprising the N-terminal tail and the three polypeptide loops is essential to the in vivo assembly of the functional rhodopsin. We now report on more comprehensive mutagenic studies in the intradiscal domain to determine more precisely the requirement for the formation of the above-proposed tertiary structure. Three large deletions, two consisting of groups of 10 amino acids each, and the third of 34 amino acids, were carried out in the N-terminal loop. All the three mutant opsins only poorly formed the rhodopsin chromophore. In the BC loop, we carried out five 2 amino acid deletions, 2 single amino acid deletions, and three mutations in which short sequences in the loop were reversed. All the resulting mutant opsins had lost the ability to bind 11-cis-retinal. In the DE loop, where extensive mutagenesis had previously been carried out, we carried out 3 amino acid replacements (Asn, Thr, Tyr) at Cys187. None of these mutants bound 11-cis-retinal. In loop FG, we carried out four 2 amino acid deletions, 1 single amino acid deletion, 3 amino acid replacements, and one mutation in which the sequence of the 7 amino acids was reversed. All the mutants in FG loop partially formed the rhodopsin chromophore. All the mutants now described appeared to be retained in the endoplasmic reticulum: several that were examined in detail were complexed with non-opsin proteins, the chaperonins. Treatment with ATP-MgCl2 released the latter from the mutant rhodopsins. Our overall conclusion is that the formation of the specific structure in the intradiscal domain has highly stringent spatial requirements.

Amino Acid Sequence↗
PubMedDate not supplied

Novel histamine H3-receptor antagonists with benzyl ether structure or related moieties: synthesis and structure-activity relationships.

In search of new histamine H3-receptor ligands sixteen ether derivatives of 3-(1H-imidazol-4-yl)propanol with benzylic partial structure or related moieties were prepared and investigated as H3-receptor antagonists. The new compounds belong to a general construction pattern developed by other histamine H3-receptor antagonists. Structural modifications were introduced in an attempt to optimize in vitro as well as in vivo activity. Structure-activity relationships of the new histamine H3-receptor antagonists are discussed. All ether derivatives showed in vitro activities in the nanomolar concentration range, but only compounds with bulky lipophilic residues were also active under in vivo conditions. The most active compound within this series was 3-(1H-imidazol-4-yl)propyl 1-naphthylmethyl ether (4n) presenting an ED50 of 3.2 +/- 1.9 mg/kg regarding enhancement of endogenous histamine in brain after p.o. administration to mice. Furthermore, comparison of the H3-receptor activities measured on synaptosomes of rat cerebral cortex and on guinea pig ileum gave a good correlation indicating homogeneity of central and peripheral H3-receptor test models. The most interesting compounds were also evaluated in functional in vitro assays with regard to their activities at histamine H1-, H2-, and muscarinic M3-receptors. The tested compounds showed very weak activities at these receptor subtypes demonstrating their H3-receptor selectivity.

Animals↗
PubMed2006

Stabilization of unusual structures in peptides using alpha,beta-dehydrophenylalanine: crystal and solution structures of Boc-Pro-DeltaPhe-Val-DeltaPhe-Ala-OMe and Boc-Pro-DeltaPhe-Gly-DeltaPhe-Ala-OMe.

The structures of two dehydropentapeptides, Boc-Pro-DeltaPhe-Val-DeltaPhe-Ala-OMe (I) and Boc-Pro-DeltaPhe-Gly-DeltaPhe-Ala-OMe (II) (Boc: t-butoxycarbonyl), have been determined by nuclear magnetic resonance (NMR), circular dichroism (CD), and X-ray crystallographic studies. The peptide I assumes a S-shaped flat beta-bend structure, characterized by two partially overlapping type II beta-bends and absence of a second 1 <-- 4 (N4--H . . . O1') intramolecular hydrogen bond. This is in contrast to the generally observed 3(10)-helical conformation in peptides with DeltaPhe at alternate positions. This report describes the novel conformation assumed by peptide I and compares it with that of the conserved tip of the V3 loop of the HIV-1 envelope glycoprotein gp120 (sequence, G:P319 to F:P324, PDB code 1ACY). The tip of the V3 loop also assumes a S-shaped conformation with Arg:P322, making an intramolecular side-chain-backbone interaction with the carbonyl oxygen of Gly:P319. Interestingly, in peptide I, C(gamma)HVal(3) makes a similar side-chain-backbone C--H . . . O hydrogen bond with the carbonyl oxygen of the Boc group. The observed overall similarity indicates the possible use of the peptide as a viral antagonist or synthetic antigen. Peptide II adopts a unique turn followed by a 3(10)-helix. Both peptides I and II are classical examples of stabilization of unusual structures in oligopeptides.

Amino Acid Sequence↗
PubMed2001

Extended quantitative structure-activity relationships for 80 aromatic and heterocyclic amines: structural, electronic, and hydropathic factors affecting mutagenic potency.

The mutagenic/carcinogenic heterocyclic amines formed during the cooking of protein foods have been determined to be probable or possible human carcinogens. As part of a comprehensive study of the food mutagens, our laboratory has produced a series of quantitative structure-activity relationships (QSARs) of aromatic and heterocyclic amines, to attempt to elucidate the mechanisms of mutagenesis/carcinogenesis. Amines are genotoxically active only after activation by a series of reactions converting the parent compound to an electrophilic derivative, which is postulated to be a nitrenium ion that covalently binds to and damages DNA. An important agent in this conversion is cytochrome P450. In this report we develop a QSAR for 80 amines of diverse structure and a range of 10 orders of magnitude in mutagenic potency. New structural factors and quantum chemical ab initio and Hückel calculations are included. The results are interpreted to show that a main determinant of mutagenic potency is the extent of the aromatic pi-electron system. Small contributions are made by both the dipole moment and the calculated stability of the nitrenium ion. Multiple linear regression models account for nearly two-thirds of the variance in potency, leaving room for additional unknown factors. The role of cytochrome P450 1A in amine toxification is supported, and further theoretical and experimental research on its reaction mechanisms and modeling of its active site are proposed.

Amines↗
PubMed1994

Crystal structure of vitelline membrane outer layer protein I (VMO-I): a folding motif with homologous Greek key structures related by an internal three-fold symmetry.

The crystal structure of vitelline membrane outer layer protein I (VMO-I), which is isolated from the vitelline membrane outer layer of hen's eggs, has been determined by the multiple isomorphous replacement method and refined to an R-factor of 18.8% at 2.2 A resolution. The main chain folds into an unusual structure that consists of three beta-sheets forming Greek key motifs, which are related by an internal pseudo three-fold symmetry. The internal portion surrounded by these three beta-sheets is filled with hydrophobic side chains. This conformational feature coincides with three internal repeats in the sequence. Although a similar fold exists in the second domain of delta-endotoxin, there are significant structural differences between the two proteins, with the three-fold symmetry being most regular in VMO-I.

Amino Acid Sequence↗
PubMed2006

Crystal structures of thymidylate synthase mutant R166Q: structural basis for the nearly complete loss of catalytic activity.

Thymidylate synthase (TS) catalyzes the folate-dependent methylation of deoxyuridine monophosphate (dUMP) to form thymidine monophosphate (dTMP). We have investigated the role of invariant arginine 166, one of four arginines that contact the dUMP phosphate, using site-directed mutagenesis, X-ray crystallography, and TS from Escherichia coli. The R166Q mutant was crystallized in the presence of dUMP and a structure determined to 2.9 A resolution, but neither the ligand nor the sulfate from the crystallization buffer was found in the active site. A second structure determined with crystals prepared in the presence of dUMP and the antifolate 10-propargyl-5,8-dideazafolate revealed that the inhibitor was bound in an extended, nonproductive conformation, partially occupying the nucleotide-binding site. A sulfate ion, rather than dUMP, was found in the nucleotide phosphate-binding site. Previous studies have shown that the substitution at three of the four arginines of the dUMP phosphate-binding site is permissive; however; for Arg166, all the mutations lead to a near-inactive mutant. The present structures of TS R166Q reveal that the phosphate-binding site is largely intact, but with a substantially reduced affinity for phosphate, despite the presence of the three remaining arginines. The position of Cys146, which initiates catalysis, is shifted in the mutant and resides in a position that interferes with the binding of the dUMP pyrimidine moiety.

Amino Acid Substitution↗
PubMed1984

Discriminative structural analysis using pattern recognition techniques in the structure-taste problem of perillartines.

Pattern recognition techniques have been applied to the study of structure-taste correlations for perillartine derivatives. The structure of each compound was described by hydrophobicity (log P), logarithm of water solubility (log S), and topological descriptors relating to some positions which were assigned by superposing each compound on a "template" structure. The fragment molecular connectivities were calculated as the topological descriptors. The discriminant functions between the sweet and bitter taste classes were computed by the use of the simplex optimization technique, which correctly recognized most of the compounds under investigation. It was found that the hydrophobicity and one or two topological descriptors concerned with a specific part of the molecules contributed significantly to the discrimination. The discriminant function obtained correctly classified seven of nine compounds (which were not involved in the data set for developing the function) into the taste class to which they belonged.

Cyclohexenes↗
PubMed1991

The concept of molecular structure in structure-activity relationship studies and drug design.

We can justify the use of any model, method, or algorithm if we clearly state our goals, understand the basis of our procedures, and fully appreciate the true nature and limitations of the results. As we have illustrated here, the creation of new wisdom may appear to be a consequence of our labors. There are cases, however, where this creation may be only an illusion. In any analysis of structure-activity, property-activity, or structure-property relationships, the degree of understanding of the nature of the starting data therefore determines the level of confidence ascribable to any result and prediction. This is, in essence, the message of our inquisitive meditations on the deep nature of structure-activity relationships.

Chemistry, Pharmaceutical↗