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Biomedical subjects

A K Ghose

Publications and source records attributed to A K Ghose.

At least 19 recordsLinked to original sources
PubMed1995

Inhibition of matrix metalloproteinases by hydroxamates containing heteroatom-based modifications of the P1' group.

In this study, structure-based drug design of matrix metalloproteinase inhibitors [human fibroblast collagenase (HFC), human fibroblast stromelysin (HFS), and human neutrophil collagenase (HNC)] was utilized in the development of potent hydroxamates which contain novel, heteroatom-based modifications of the P1' group. A series containing a P1' butyramide group resulted in a nanomolar potent and selective HNC inhibitor as well as a dual HFS/HNC inhibitor. Benzylic ethers with a four- or five-carbon methylene linker in the P1' position also produced nanomolar potent HFS/HNC inhibition and micromolar potent HFC inhibition as expected. Surprisingly, the phenolic ethers of the same overall length as the benzylic ethers showed nanomolar potencies against HFC, as well as HFS and HNC. The potency profile of the phenolic ethers was optimized by structure-activity relationships of the phenolic group and the C-terminal amide. These inhibitors may help elucidate the in vivo roles of matrix metalloproteinases in normal and disease states.

Crystallography, X-Ray↗
PubMed1991

Synthesis, characterization, and antitumor activity of 5-iodouracil complexes.

Complexes of 5-iodouracil (5IU) with Mn(II), Co(II), Cu(II), Zn(II), and Cd(II) ions have been prepared, characterized, and subjected to a screening system for evaluation of antitumor activity against Sarcoma-180 (S-180) and L 929 tumor cells. The complexes were characterized by their elemental analysis, infrared spectra, electronic spectra, magnetic measurements, and powder x-ray diffraction. The antitumor activity results indicate that some complexes have good antitumor activity both in vivo and in vitro against S-180 and L 929 tumor cells.

Animals↗
PubMed1991

Analysis of the in vitro antitumor activity of novel purine-6-sulfenamide, -sulfinamide, and -sulfonamide nucleosides and certain related compounds using a computer-aided receptor modeling procedure.

The comparative antileukemic activities of 21 novel nucleosides were determined in vitro by using cultured L1210 cells and analyzed for structure-related efficacy by a computer-aided receptor modeling method (REMOTEDISC) as recently described (Ghose, A. K.; et al. J. Med. Chem. 1989, 32, 746). The algorithm can be classified as a 3D-QSAR method and consists of the following steps: selection of a reference structure from the low-energy conformations of the active compounds; an automated superposition of the low-energy conformations of the other compounds so that there is maximum matching (or overlapping) of the atom-based physicochemical properties; construction of the binding-site cavity from the location of the atoms of the superimposed molecules; and determinations of the relative importance of the various physicochemical properties at different regions of the site cavity using reverse stepwise regression analysis. The model was based on the minimum energy conformation of (R,S)-2-amino-9-beta-D-ribofuranosylpurine-6-sulfinamide (sulfinosine, 5), an effective antileukemic agent in vivo, in the data set. The model fit the biological data with a standard deviation of 0.363, a correlation coefficient of 0.933 and a explained variance of 0.815. The method targeted a syn conformation as the probable active form and the 2'-OH, 5'-OH as well as C2-NH2 group of the purine ring as favoring the stability of the syn conformation, thereby establishing the major contributions of these three molecular entities to overall antitumor activity.

Animals↗
PubMed1990

Mapping the binding site of the nucleoside transporter protein: a 3D-OSAR study.

The nucleoside transporter is an intrinsic membrane protein that mediates salvage of nucleosides from the extracellular medium. In this report, its binding sites have been characterized by a 3D-QSAR (three-dimensional structure-directed quantitative structure-activity relationships) receptor mapping technique. REMOTEDISC. The algorithm is applied to a set of 19 nucleoside analogues, each of which binds to the transporter. The methodology includes: (i) conformational analysis of each ligand; (ii) estimation of physicochemical properties of each ligand at the atomic level; (iii) structural comparison of the low energy conformation of each ligand in the series with a reference structure on the basis of physicochemical property matching; (iv) construction of a predicted binding site cavity from the alignments of step (iii); and (v) multiple regression analysis of the binding data with respect to the 3-dimensional physicochemical descriptors in different 'site-pockets' of the binding cavity. The pharmacophore model that emerges consists of the geometry of the binding site cavity and the relative weights of various properties in different pockets for each of the ligands considered. The study suggests that binding free energy is sensitive to the composition, size and hydrophobicity of the heterocyclic base in the ligand. Though both syn and anti conformations are tried as active forms, the anti conformation gives a better solution and is chosen for modeling the binding site cavity. The best model obtained divides the binding site into six pockets and uses nine independent variables, fitting the observed data with a correlation coefficient of 0.94, a standard deviation of 0.22 and an explained variance of 0.80. Results of our model are consistent with a hypothesis that the 5'-OH group hydrogen bonds with the receptor. This model provides tentative design criteria for development of new nucleoside drugs and transport inhibitors. The model will undoubtedly continue to evolve (i) as the 3D-QSAR algorithm is further refined, and (ii) as data on additional nucleoside analogues become available.

Algorithms↗
PubMed1990

Modeling the benzodiazepine receptor binding site by the general three-dimensional structure-directed quantitative structure-activity relationship method REMOTEDISC.

A novel computer-aided receptor modeling method, REMOTEDISC [J. Med. Chem. 32:746-756 (1989)], has been used to analyze the inhibition of labeled diazepam binding by 29 benzodiazepine receptor ligands. The method uses the three-dimensional structure, conformational energy, and important atom-based physicochemical properties to model the hypothetical binding site cavity. The model not only consists of the geometry of the binding cavity but also gives the weight of the various physicochemical properties of the ligands at different parts of the binding cavity responsible for their binding to the receptor. The model fitted the binding data with a correlation coefficient of 0.980, a SD of 0.223, and an explained variance of 0.898. It suggested that a small hydrophilic group is favored at position 1 of the benzodiazepine ring, the C = O region of this ring is favored by dispersive atoms and positive charge, the 4'-substituent of the 5-phenyl group is subject to strong steric repulsion, the 7- position is favored to be a hydrophilic group, and the 8- and 9- positions and their substituents are favored to be dispersive as well as hydrophilic groups. It also suggested that the substitution of the 5-phenyl group by the more dispersive 2-thiophene may increase the binding affinity. The model was allowed to predict the binding affinity data of five compounds with extensive variation of the structure from the training set; the prediction for four compounds was excellent. Some of the problems of the method have been discussed with their possible remedies.

Benzodiazepines↗
PubMed1989

The effect of histidine on the structure and antitumor activity of metal-5-halouracil complexes.

The ternary complexes of Mn(II), Co(II), Ni(II), Cu(II), Zn(II), and Cd(II) ions with 5-halouracils, viz., 5-fluorouracil (5FU), 5-chlorouracil (5ClU), and 5-bromouracil (5BrU), and the biologically important ligand L-histidine (HISD) have been synthesized and characterized by elemental analysis, conductance measurements, infrared spectra, electronic spectra, and magnetic moment (room temperature) measurements. On the basis of these studies, the structures of the complexes have been proposed. All these ternary complexes were screened for their antitumor activity against Dalton's lymphoma in C3H/He mice. It was found that only Mn(II)-5BrU-HISD, Co(II)-5BrU-HISD, Cu(II)-5ClU-HISD, Cu(II)-5BrU-HISD, Zn(II)-5FU-HISD, and Zn(II)-5BrU-HISD complexes have significant antitumor activity with T/C greater than 125% (where T and C represent mean lifespan of treated mice and control mice respectively). The Mn(II)-5FU-HISD, Co(II)-5FU-HISD, Co(II)-5ClU-HISD, Ni(II)-5ClU-HISD, Ni(II)-5BrU-HISD, and Zn(II)-5ClU-HISD complexes are also effective antitumor agents, with T/C greater than 115%. The complexes that showed effective antitumor action in vivo were also found to inhibit 3H-thymidine incorporation (DNA replication) in Dalton's lymphoma cells in vitro.

Animals↗
PubMed1989

Analysis of the in vitro antiviral activity of certain ribonucleosides against parainfluenza virus using a novel computer aided receptor modeling procedure.

The in vitro antiviral activity of 28 nucleosides against the parainfluenza virus type 3 has been analyzed by using a novel computer aided receptor modeling procedure. The method involves an extensive modification of our earlier work (Ghose, A. K.; Crippen, G. M. J. Med. Chem. 1985, 28, 333). It presents a more straightforward algorithm for the steps that suffered from subjectivity in the earlier method. The method first determines the possible low-energy conformations of the nucleosides, and assigns a priority value for each conformation of each molecule. It then performs the following steps repeatedly, until it finds an acceptable solution. Starting from the conformation of highest priority, the various energetically allowed conformations of the other molecules are superimposed on it. On the basis of the physicochemical property matching (or overlapping), the best superposition is determined. The superimposed molecules are dissected into a minimum number of parts and the local physicochemical properties at different regions are correlated with their binding data (antiviral activity). A modified version of distance geometry has been used for geometric comparison of the structure of the molecules. On the basis of the virus rating (VR) of 28 ribonucleosides, this procedure hypothesized the minimum-energy conformation of 6-(methylthio)-9-beta-D-ribofuranosylpurine as a reference conformation and used three physicochemical properties, namely hydrophobicity, molar refractivity, and formal charge density for property matching. The binding-site cavity was divided into seven regions or pockets to differentiate the nature of interaction quantitatively. The model suggests that the 2- and 3-positions of the purine ring and the corresponding atoms of the other rings get some steric repulsion, and nucleosides having a single five-membered heterocyclic ring will better fit this virus. The methylthio group gets a strong attraction from dispersive interaction. Both hydrophilic and dispersive groups are attractive here. Although our calculation supports the previously suggested active conformation of ribavirin, it shows that it is not the global minimum-energy conformation. The difference lies in the orientation of the amide group. The calculated viral rating from this model showed a correlation coefficient of 0.971 with the observed values, and the explained variance and the standard deviation of the fit were 0.880 and 0.125, respectively.

Antiviral Agents↗
PubMed1989

Structural mimicry of adenosine by the antitumor agents 4-methoxy- and 4-amino-8-(beta-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine as viewed by a molecular modeling method.

A rationale for the antitumor activity of 4-methoxy- and 4-amino-8-(beta-D-ribofuranosylamino)pyrimido-[5,4-d]pyrimidine (beta-MRPP and beta-ARPP, respectively) was studied by a molecular modeling method. Although these nucleoside analogues are structurally different from adenosine, they act as substrates for adenosine kinase. The molecular modeling method, which considered the three-dimensional structure and atom-based physicochemical properties of the nucleosides to quantify the molecular similarities, showed that certain low-energy conformations of the beta anomers of a series of nucleosides including beta-MRPP, beta-ARPP, and their 4-hydroxy, 4-amino-6-chloro, 4-methylthio-2,6-dichloro, 4,6-diamino, 4-dimethylamino, 4-methylamino, and 4-hydroxy-2,6-dichloro analogues have remarkable structural similarity to adenosine. The method also suggested that the selection of the reference compound adenosine in the structural comparison is of primary importance to gain insight into the observed antitumor activity. The success of the present method led to AM1 (Austin model 1) molecular orbital calculations and experimental studies indicating that the antitumor activity of the alpha anomer of ARPP is probably due to equilibration to the beta anomer. The AM1 calculation of the protonation energy of N5 of pyrimido[5,4-d]pyrimidines, which occupies the same position in space as the N1 of adenosine, gave a direct correlation between the basicity of the nitrogen with a lone pair of electrons and the observed antitumor activity.

Adenosine↗
PubMed1987

Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 2. Modeling dispersive and hydrophobic interactions.

In an earlier paper (Ghose A. K.; Crippen, G. M. J. Comput. Chem. 1986, 7, 565) the need of atomic physicochemical properties for three-dimensional-structure-directed quantitative structure-activity relationships was demonstrated, and it was shown how atomic parameters can be developed to successfully evaluate the molecular water-1-octanol partition coefficient, which is a measure of hydrophobicity. In the present work the atomic values of molar refractivity are reported. Carbon, hydrogen, oxygen, nitrogen, sulfur, and halogens are divided into 110 atom types of which 93 atomic values are evaluated from 504 molecules by using a constrained least-squares technique. These values gave a standard deviation of 1.269 and a correlation coefficient of 0.994. The parameters were used to predict the molar refractivities of 78 compounds. The predicted values have a standard deviation of 1.614 and a correlation coefficient of 0.994. The degree of closeness of the linear relationship between the atomic water-1-octanol partition coefficients and molar refractivities has been checked by the correlation coefficient of 89 atom types used for both the properties. The correlation coefficient has been found to be 0.322. The low value suggests that both parameters can be used to model the intermolecular interaction. The origin of these physicochemical properties and the types of interaction that can be modeled by these properties have been critically analyzed.

Models, Theoretical↗
PubMed1985

Use of physicochemical parameters in distance geometry and related three-dimensional quantitative structure-activity relationships: a demonstration using Escherichia coli dihydrofolate reductase inhibitors.

In earlier distance geometry related three-dimensional quantitative structure-activity relationships (Ghose, A. K.; Crippen, G. M. J. Med. Chem. 1984, 27, 901) the interactions of the ligand atom or group with the receptor site were evaluated empirically by using mathematical optimization techniques, without considering their physicochemical properties. In the present work we show how to use various physicochemical parameters in our three-dimensional receptor mapping. We have developed a model for E. coli DHFR using the inhibition data of 25 pyrimidines and 14 triazines. It gave a correlation coefficient of 0.893 and standard deviation of 0.530. It successfully predicted the binding data of five pyrimidines and five triazines.

Binding Sites↗
PubMed1984

General distance geometry three-dimensional receptor model for diverse dihydrofolate reductase inhibitors.

A common three-dimensional receptor model has been formulated for six different classes of rat liver dihydrofolate reductase inhibits using the distance geometry approach. Altogether, 62 molecules of five different classes were used to generate the receptor model, which has 11 attractive site points and 5 repulsive ones. It gave a fit having a correlation coefficient of 0.949 and root mean square (rms) deviation of 0.527. The attractive site points of the model closely correspond to the one we reported earlier. The model successfully predicted the biological data of 33 molecules of 5 different classes, one molecule of which was a member of a new class not included in the original data set. Guidelines are put forth for the synthesis of improved inhibitors.

Animals↗
PubMed1983

Combined distance geometry analysis of dihydrofolate reductase inhibition by quinazolines and triazines.

Guided by the success of distance geometry in explaining the inhibition of dihydrofolate reductase by 68 quinazolines, we have made a combined analysis on the inhibition of rat liver dihydrofolate reductase by 33 triazines and 15 quinazolines. The model gave a fit having the correlation coefficient 0.892 and root mean square (rms) deviation 0.596 in log (1/C50) units. The model was applied to predict the biological activity of 91 compounds. The predicted values showed an rms deviation of 0.907 and a correlation coefficient of 0.790. The present study suggested the synthesis of some triazines as possible potent dihydrofolate inhibitors. The site geometry was compared with the crystal structure of a triazine bound to chicken liver dihydrofolate reductase, and a good correlation has been found.

Chemical Phenomena↗
PubMed1982

Quantitative structure-activity relationship by distance geometry: quinazolines as dihydrofolate reductase inhibitors.

This is a reinvestigation of 68 quinazoline inhibitors of dehydrofolate reductase. As in the earlier study, the binding data fitted to an 11-point model of the site, but improved computer algorithms resulted in a much better overall fit (correlation coefficient 0.95, standard deviation 0.727 kcal) and a more accurate fit for some very loosely bound 2,4-diaminoquinazolines. Removal of two of the site points (numbers 5 and 9) gave an even better fit than the original 11 site points. However, deleting a third one (number 8) worsened the calculated binding energies of the loosely bound 2,4-diaminoquinazolines. The results lead to predictions of chemical modifications of the quinazolines that should improve their biological activity.

Chemical Phenomena↗