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R Langridge

Publications and source records attributed to R Langridge.

At least 37 records · Page 2Linked to original sources
PubMed1987

Concanavalin X-phenyl beta-D-glucopyranoside interactions. A molecular graphics-QSAR analysis.

Poretz and Goldstein showed that X-phenyl beta-D-glucopyranosides prevent the agglutination of concanavalin A with polysaccharides and derived inhibition constants for the process. Using their data the binding of 25 glucosides to concanavalin is now shown to be correlated with the molar refractivity of the substituents on the phenyl ring. This is interpreted to mean that it is the bulk of the substituents and not their hydrophobicity which prevents the union of concanavalin and the polysaccharide. These results are similar to those found for other haptens preventing antibody-antigen interaction.

Concanavalin A↗
PubMed1986

Molecular mechanics studies of dermorphin.

Molecular mechanical simulations have been carried out on dermorphin. Presence of D-Ala2 at the N-terminus and L-Pro6 residue at the C-terminus indicated the probability of beta-turns. From the stereochemical considerations, three types- II', III' and V' - for the beta-turn at the N-terminus of the peptide and two types-I and III- for the C-terminus side of the peptide are possible. In our molecular mechanics calculations, we considered six folded and one extended conformations for dermorphin to asses the relative stabilities. Three of the six folded conformations are lower in energy and have the following general feature-similar in energy, three hydrogen bonds, semirigid beta-sheet segment and favorable Tyr1-Tyr5 interaction. The presence of beta-sheet structure might play a role in mu-receptor selective interaction of dermorphin.

Analgesics, Opioid↗
PubMed1986

A quantitative structure-activity relationship and molecular graphics analysis of hydrophobic effects in the interactions of inhibitors with alcohol dehydrogenase.

An analysis of the inhibition constants of pyrazoles, phenylacetamides, formylbenzylamines, and acetamides acting on liver alcohol dehydrogenase (ADH) yields quantitative structure-activity relationships (QSAR) having a linear dependency on octanol-water partition coefficients (log P). The average coefficient and standard deviation with the log P term for six different QSAR is 0.96 (+/- 0.14). This suggests complete desolvation of the substituents (directly comparable to partitioning into octanol) on binding to the enzyme. Study of a molecular graphics model of ADH constructed from the X-ray crystallographic coordinates shows that the substituents are engulfed in a long hydrophobic channel which is so narrow that water of solvation must be removed from them in the binding process.

Acetamides↗
PubMed1986

Inhibition of chicken liver dihydrofolate reductase by 5-(substituted benzyl)-2,4-diaminopyrimidines. A quantitative structure-activity relationship and graphics analysis.

The inhibition of chicken liver dihydrofolate reductase by a series of substituted benzylpyrimidines has been investigated. From the inhibition constants a quantitative structure-activity relationship has been formulated. This mathematical model is compared with molecular graphics models constructed from the X-ray crystallographic coordinates of trimethoprim and 5-(3,4-dimethoxy-4-isopropenylbenzyl)-2,4- diaminopyrimidine bound to the enzyme. There is good correspondence between the two types of models.

Animals↗
PubMed1986

Molecular mechanical studies of d(CGTACG)2: complex of triostin A with the middle A - T base pairs in either Hoogsteen or Watson-Crick pairing.

Computer graphics model building and molecular mechanical calculations have been carried out on d(CGTACG)2 and its bis-intercalation complexes with triostin A and an N-Me-Ala analogue of triostin A. Two conformations of the DNA have been considered both for the uncomplexed and for complexed nucleic acid: in one the central A - T base pairs are Watson-Crick base paired; in the other they are Hoogsteen base paired. The calculations offer a clear explanation why Hoogsteen base pairing is not favorable in isolated A + T-rich DNA and also suggest reasons why the bis-intercalation of triostin A might help stabilize the neighboring A - T base pairs into a Hoogsteen form. To our knowledge, this is the first study to use molecular mechanical and dynamical methods to investigate the bis-intercalator-DNA complex.

Base Composition↗
PubMed1986

Quantitative structure-activity relationships and molecular graphics in ligand receptor interactions: amidine inhibition of trypsin.

Quantitative structure-activity relationships have been formulated for four sets of amidine inhibitors of trypsin. The quantitative results from these equations are compared with qualitative models constructed from the X-ray crystallographic coordinates of a benzamidine bound to trypsin. The good agreement between the mathematical and graphics models provides further support for the use of substituent constants and regression analysis in the study of enzyme-ligand interactions.

Amidines↗
PubMed1985

Molecular basis for the transfer of nicotinamide adenine dinucleotide among dehydrogenases.

NADH is transferred directly from one dehydrogenase enzyme site to another without intervention of the aqueous solvent whenever the two dehydrogenases are of opposite chiral specificity as regards the C4 H of NADH which is transferred in the catalyzed reduction reaction. When both enzymes catalyze the transfer of hydrogen from the same face of the nicotinamide ring, direct enzyme-enzyme transfer of NADH is not possible [Srivastava, D. K., & Bernhard, S. A. (1984) Biochemistry 23, 4538-4545; Srivastava, D. K., & Bernhard, S. A. (1985) Biochemistry (preceding paper in this issue)]. Utilizing an advanced computer graphics facility, and the known three-dimensional coordinates for three dehydrogenases, we have investigated the feasibility of various aspects of the direct transfer of dinucleotide from the site of one enzyme to the site of the other. The facile passage of the coenzyme through the first enzyme site requires an open protein conformation, characteristic of the apoenzyme rather than the holoenzyme structure. Since two dehydrogenases of the same chirality bind coenzyme in the same conformation, the direct transfer of coenzyme from one site to the other is impossible due to the restriction in molecular rotation of the coenzyme in the path of transfer from one binding site to the other; therefore, coenzyme can only be transferred from one dehydrogenase site to another site via the intermediate dissociation of coenzyme into the aqueous milieu. In contrast, when an A dehydrogenase and a B dehydrogenase are juxtaposed, it is stereochemically feasible to transfer the nicotinamide ring from its specific binding site in one enzyme to the site in the other.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Dehydrogenase↗
PubMed1985

Flexibility of 3',5' deoxyribonucleoside diphosphates.

In 3',5' deoxyribonucleoside diphosphates, in addition to the nature of the base and the sugar puckering, there are six single bond rotations. However, from the analysis of crystal structure data on the constituents of nucleic acids, only three rotational angles, that are about glycosyl bond, about C4'-C5' and about C3'-O3' bonds, are flexible. For a given sugar puckering and a base, potential energy calculations using non-bonded, electrostatic and torsional functions were carried out by varying the three torsion angles. The energies are represented as isopotential energy surfaces. Since the availability of the real-time color graphics, it is possible to analyse these isopotential energy surfaces. The calculations were carried out for C3' exo and C3' endo puckerings for deoxyribose and also for four bases. These calculations throw more light not only on the allowed regions for the three rotational angles but also on the relationships among them. The dependence of base and the puckering of the sugar on these rotational angles and thereby the flexibility of the 3',5' deoxyribonucleoside diphosphates is discussed. From our calculations, it is now possible to follow minimum energy path for interconversion among various conformers.

Deoxyribonucleotides↗
PubMed1985

Interactions of Streptomyces subtilisin inhibitor with Streptomyces griseus proteases A and B. Enzyme kinetic and computer simulation studies.

Streptomyces subtilisin inhibitor (SSI), a dimeric protein that strongly inhibits subtilisins, was shown to form tight inhibitory complexes with Streptomyces griseus proteases A and B (SGPA and SGPB). The apparent dissociation constants of the SGPA-SSI and SGPB-SSI complexes were found to be orders of magnitude less than those of subtilisin-SSI complexes. Using the known atomic coordinates for SGPA and SSI, the highly complementary nature of the surface geometries of the two proteins was confirmed by a computer graphics study, which led to a proposed structure for the SGPA-SSI complex. Kinetic studies further suggested that the SSI dimer can bind two molecules of either SGPA or SGPB, and the 2:1-complexes (consisting of one inhibitor dimer and one enzyme molecule) apparently possess lower intrinsic dissociation constants than the 2:2-complexes. It was also shown that both of SGPA and SGPB are inhibited by both soybean trypsin inhibitor (Kunitz) and bovine pancreatic trypsin inhibitor (Kunitz), but far less strongly than by SSI.

Aspartic Acid Endopeptidases↗
PubMed1985

A quantitative structure-activity relationship and molecular graphics study of carbonic anhydrase inhibitors.

A quantitative structure-activity relationship (QSAR) (log K = 1.55 alpha + 0.64 log P - 2.07I1 - 3.28I2 + 6.94) has been formulated for the binding of a set of substituted benzenesulfonamides to human carbonic anhydrase. The binding constant (K) are from the studies of King and Burgen [Proc. R. Soc. Lond. B. 193:107-125 (1976)], sigma is the Hammett electronic substituent constant, P is the octanol/water partition coefficient, and I1 and I2 are indicator variables for meta and ortho substituents, respectively. The negative coefficients with the indicator variables suggest steric hindrance by these substituents in contrast to para substituents. Qualitative features of the QSAR are correlated with a color stereomolecular graphics model of the enzyme-inhibitor complex which was constructed from the X-ray crystallographic coordinates of the enzyme.

Carbonic Anhydrase Inhibitors↗
PubMed1984

Papain hydrolysis of X-phenyl-N-methanesulfonyl glycinates: a quantitative structure-activity relationship and molecular graphics analysis.

The hydrolysis of 32 X-phenyl-N-methanesulfonyl glycinates by papain was investigated. It was found that the variation in the Michaelis constants could be rationalized by the following correlation equation: log 1/Km = 0.61 pi '3 + 0.46 MR4 + 0.55 sigma + 2.00 with a correlation coefficient of 0.945. In this expression, pi '3 is the hydrophobic constant for the more lipophilic of the two possible meta substituents, MR4 is the molar refractivity of 4-substituents, and sigma is the Hammett constant summed for all substituents. Using this equation, we designed, synthesized, and successfully predicted Km for a new congener intended to maximize binding (1/Km). The interactions involved in enzyme-substrate binding, as characterized by the correlation equation, are interpreted using a computer-constructed color three-dimensional-graphics molecular model of the enzyme active site. The nonenzymatic hydrolysis (both acid and basic) of phenyl hippurates yield rate constants which are well correlated by Hammett equations; however, log k for both acid and alkaline hydrolysis are not linearly related to log 1/Km or log kcat/Km.

Binding Sites↗
PubMed1984

Crystallography, quantitative structure-activity relationships, and molecular graphics in a comparative analysis of the inhibition of dihydrofolate reductase from chicken liver and Lactobacillus casei by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazine s.

The inhibition of dihydrofolate reductase from chicken liver and from Lactobacillus casei has been studied with 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazines. It was found that for the chicken enzyme, inhibitor potency for 101 triazines was correlated by the following equation: log 1/Kiapp = 0.85 sigma tau' - 1.04 log (beta X 10 sigma tau' + 1) + 0.57 sigma + 6.36. The parameter tau' indicates that for certain substituents, tau = 0. In the case of the L. casei DHFR results, meta and para derivatives could not be included in the same equation. For 38 meta-substituted compounds, it was found that log 1/Kiapp = 0.38 tau'3-0.91 log (beta X 10 tau'3 + 1) + 0.71I + 4.60 and for 32 para-substituted phenyltriazines log 1/Kiapp = 0.44 tau'4-0.65 log (beta tau'4 + 1') - 0.90 upsilon + 0.69I + 4.67. In the L. casei equation, I is an indicator variable for substituents of the type CH2ZC6H4-Y and ZCH2C6H4-Y, where Z = O, NH, S, or Se. The parameter upsilon is Charton's steric parameter, which is similar to Taft's Es. The mathematical models obtained from correlation analysis are compared with stereo color graphics models.

Animals↗
PubMed1984

An iterative approach to placing counterions around DNA.

An iterative approach, in which the effect of placing counter ions around DNA influences the electrostatic potential that the other subsequently approaching ions feel, has been used to place sodium ions around polynucleotides. The main focus of this report is to study the sequence and structure dependence on the distribution of ions around DNA, particularly that of tightly bound ions. The interesting results of the calculations are that there is significant sequence dependence on the electrostatic potentials in the B form of DNA, whereas relatively less difference in A form. In the case of Z form, the cations bridge the inter-stand phosphates along the minor groove.

Base Composition↗
PubMed1982

Comparison of the inhibition of Escherichia coli and Lactobacillus casei dihydrofolate reductase by 2,4-diamino-5-(substituted-benzyl)pyrimidines: quantitative structure-activity relationships, X-ray crystallography, and computer graphics in structure-activity analysis.

The inhibition constants (Kiapp) obtained from the action of 44 2,4-diamino-5-(substituted-benzyl)pyrimidines on dihydrofolate reductase (DHFR) from Escherichia coli and Lactobacillus casei bacteria are used to derive quantitative structure-activity relationships (QSAR). These equations bring out a number of differences in the DHFR which can be understood at the atomic level by studying color stereo computer graphics models constructed from the X-ray coordinates of the enzyme-inhibitor complexes. The combination of QSAR and X-ray crystallography interpreted via high-performance computer graphics offers a new level of sophistication to extend our understanding of enzyme-ligand interactions, which, when the crystallography is known, opens up a more scientific approach to drug development.

Binding Sites↗