Biomedical subjects

A K Debnath

Publications and source records attributed to A K Debnath.

At least 19 recordsLinked to original sources

PubMed2001

Cellulose acetate phthalate, a common pharmaceutical excipient, inactivates HIV-1 and blocks the coreceptor binding site on the virus envelope glycoprotein gp120.

BACKGROUND: Cellulose acetate phthalate (CAP), a pharmaceutical excipient used for enteric film coating of capsules and tablets, was shown to inhibit infection by the human immunodeficiency virus type 1 (HIV-1) and several herpesviruses. CAP formulations inactivated HIV-1, herpesvirus types 1 (HSV-1) and 2 (HSV-2) and the major nonviral sexually transmitted disease (STD) pathogens and were effective in animal models for vaginal infection by HSV-2 and simian immunodeficiency virus. METHODS: Enzyme-linked immunoassays and flow cytometry were used to demonstrate CAP binding to HIV-1 and to define the binding site on the virus envelope. RESULTS: 1) CAP binds to HIV-1 virus particles and to the envelope glycoprotein gp120; 2) this leads to blockade of the gp120 V3 loop and other gp120 sites resulting in diminished reactivity with HIV-1 coreceptors CXCR4 and CCR5; 3) CAP binding to HIV-1 virions impairs their infectivity; 4) these findings apply to both HIV-1 IIIB, an X4 virus, and HIV-1 BaL, an R5 virus. CONCLUSIONS: These results provide support for consideration of CAP as a topical microbicide of choice for prevention of STDs, including HIV-1 infection.

Anti-HIV Agents↗

PubMed2001

Quantitative structure-activity relationship (QSAR) paradigm--Hansch era to new millennium.

The analysis of structure-activity relationships started probably more than hundred years ago but the concept of quantitatively correlating physicochemical properties of molecules with their biological activities, termed as quantitative structure-activity relationship (QSAR), was initiated by Corwin Hansch and his groups in early 1960. Many new methods have emerged since then. The concept evolved from 2D QSAR to 3D QSAR and lately another dimension (4D QSAR) has been added. This evolution is briefly reviewed here.

Animals↗

PubMed2000

A salt bridge between an N-terminal coiled coil of gp41 and an antiviral agent targeted to the gp41 core is important for anti-HIV-1 activity.

HIV-1 envelope glycoprotein transmembrane subunit gp41 play a critical role in the fusion of viral and target cell membranes. The gp41 C-terminal heptad repeat region interacts with the N-terminal coiled-coil region to form a six-stranded core structure. Peptides derived from gp41 C-terminal heptad repeat region (C-peptides) are potent HIV-1 entry inhibitors by binding to gp41 N-terminal coiled-coil region. Most recently, we have identified two small organic compounds that inhibit HIV-1-mediated membrane fusion by blocking the formation of gp41 core. These two active compounds contain both hydrophobic and acidic groups while the inactive compounds only have hydrophobic groups. Analysis by computer modeling indicate that the acidic groups in the active compounds can form salt bridge with Lys 574 in the N-terminal coiled-coil region of gp41. Asp 632 in a C-peptide can also form a salt bridge with Lys 574. Replacement of Asp 632 with positively charged residues or hydrophobic residues resulted in significant decrease of HIV-1 inhibitory activity. These results suggest that a salt bridge between an N-terminal coiled coil of the gp41 and an antiviral agent targeted to the gp41 core is important for anti-HIV-1 activity.

Amino Acid Sequence↗

PubMed2000

Development of HIV entry inhibitors targeted to the coiled-coil regions of gp41.

The discoveries that synthetic peptides corresponding to the N- and C-terminal heptad repeat (HR) regions of gp41 have potent anti-HIV activity opened a new avenue to identification of small molecule HIV entry inhibitors targeted to the HIV gp41 coiled-coil regions. Based on the structural information of the HIV gp41 core, three distinct approaches to develop small molecule anti-HIV agents have been reported. Each of these approaches has specific advantages, which will have complementary effects on the design of new strategies for identification of more potent HIV entry inhibitors. It is expected that novel antiviral drugs targeted to the HIV gp41 coiled-coil regions will be developed in the near future for the chemotherapy and/or prophylaxis of HIV infection and AIDS.

Amino Acid Sequence↗

PubMed1999

Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1.

Recent X-ray crystallographic determination of the HIV-1 envelope glycoprotein gp41 core structure opened up a new avenue to discover antiviral agents for chemotherapy of HIV-1 infection and AIDS. We have undertaken a systematic study to search for anti-HIV-1 lead compounds targeted to gp41. Using molecular docking techniques to screen a database of 20 000 organic molecules, we found 16 compounds with the best fit for docking into the hydrophobic cavity within the gp41 core and with maximum possible interactions with the target site. Further testing of these compounds by an enzyme-linked immunosorbent assay and virus inhibition assays discerned two compounds (ADS-J1 and ADS-J2) having inhibitory activity at micromolar concentrations on the formation of the gp41 core structure and on HIV-1 infection. These two compounds will be used as leads to design more effective HIV-1 inhibitors targeted to the HIV-1 gp41 core structure.

Anti-HIV Agents↗

PubMed1999

Three-dimensional quantitative structure-activity relationship study on cyclic urea derivatives as HIV-1 protease inhibitors: application of comparative molecular field analysis.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been developed using comparative molecular field analysis (CoMFA) on a large data set (118 compounds) of diverse cyclic urea derivatives as protease inhibitors against the human immunodeficiency virus type 1 (HIV-1). X-ray crystal structures of HIV-1 protease bound with this class of inhibitors were used to derive the most probable bioactive conformations of the inhibitors. The enzyme active site was used as a constraint to limit the number of possible conformations that are sterically accessible. The test sets have been created keeping in mind structural diversity as well as the uniform simple statistical criteria (mean, standard deviation, high and low values) of the protease inhibitory activities of the molecules compared to the training sets. Multiple predictive models have been developed with the training sets (93 compounds in each set) and validated with the corresponding test sets (25 compounds in each set). All the models yielded high predictive correlation coefficients (q2 from 0.699 to 0.727), substantially high fitted correlation coefficients (r2 from 0.965 to 0.973), and reasonably low standard errors of estimates (S from 0. 239 to 0.265). The steric and electrostatic effects have approximately equal contributions, 45% and 55% (approximately), respectively, toward explaining protease inhibitory activities. This analysis yielded models with significant information on steric and electrostatic interactions clearly discerned by the respective coefficient contour plots when overlapped on the X-ray structure of the HIV-1 protease. The HINT CoMFA study revealed significant contribution of hydrophobicity toward protease inhibitory activity. The 3D visualization technique utilizing these contour plots as well as the receptor site geometry may significantly improve our understanding of the inhibitor-protease (HIV-1) interactions and help in designing compounds with improved activity.

Anti-HIV Agents↗

PubMed1999

A screening assay for antiviral compounds targeted to the HIV-1 gp41 core structure using a conformation-specific monoclonal antibody.

The human immunodeficiency virus type 1 (HIV-1) gp41 plays an important role in membrane fusion between viruses and target cells. The gp41 ectodomain contains two heptad repeat regions adjacent to the N and C-termini. Peptides derived from these two regions, designated N and C-peptides, are potent inhibitors of HIV-1 infection and can interact with each other to form a six-stranded coiled-coil, representing the fusogenic core structure of gp41. A monoclonal antibody was generated, designated NC-1, which specifically binds to the complex formed by the N and C-peptides, but not to the individual peptides. An enzyme linked immunosorbent assay (ELISA) was developed using NC-1 for detecting complex formed by N and C-peptides and for screening of organic compounds for antiviral agents that may interfere with complex formation and inhibit HIV-1 infection. Single point mutations in the C-peptides abolish the complex formation also eliminate their anti-HIV-1 activity. A phenylazo-naphthalene sulfonic acid derivative, designated ADS-J1, was found to inhibit both formation of NC-1 detectable complex and HIV-1-mediated membrane fusion, suggesting that the described ELISA is applicable to rapid screening of libraries of organic compounds for HIV-1 inhibitors targeted to the HIV-1 gp41 core structure.

Amino Acid Sequence↗

PubMed1996

Bovine beta-lactoglobulin modified by 3-hydroxyphthalic anhydride blocks the CD4 cell receptor for HIV.

Sexual transmission is the most frequent (86%) route of adult HIV-1 transmission worldwide. In the absence of a prophylactic anti-HIV vaccine, other methods of preventing infection should be implemented. Virucidal spermicides have been considered for this purpose, but their application is contraindicated by adverse effects. Anti-HIV drugs or virus-neutralizing monoclonal antibodies are expensive, suggesting that their wide use in topical chemoprophylaxis is unlikely. This emphasizes the importance of developing other methods for preventing HIV transmission. The target cells for sexual and mucosal HIV transmission include T lymphocytes, monocytes/macrophages and dendritic cells. Therefore, compounds blocking HIV-CD4 binding are expected to inhibit virus transmission. In exploring the possibility that chemical modification of food proteins might lead to compounds with anti-HIV-1 activity, we found that bovine beta-lactoglobulin (beta-LG) modified by 3-hydroxyphthalic anhydride (3HP-beta-LG) (1) blocked at nanomolar concentrations the binding to CD4 of human (HIV) and simian (SIV) immunodeficiency virus surface glycoproteins and monoclonal antibodies specific for the HIV binding site on CD4 and (2) inhibited infection by HIV-1, including primary virus isolates, by HIV-2 and by SIV. The inexpensive and widely available source (whey) for production of 3HP-beta-LG suggests its potential application (nonparenteral) for diminishing the frequency of HIV transmission.

Antiviral Agents↗

PubMed1994

Three-dimensional structure-activity analysis of a series of porphyrin derivatives with anti-HIV-1 activity targeted to the V3 loop of the gp120 envelope glycoprotein of the human immunodeficiency virus type 1.

Using comparative molecular field analysis (CoMFA), a 3D-QSAR model was developed for 21 porphyrin derivatives which have anti-HIV-1 activity and bind to the V3 loop of the envelope glycoprotein gp120 of the human immunodeficiency virus type 1. A significant PLS cross-validated r2cv (0.590) was obtained, indicating that the model could be used as a predictive tool for further design of porphyrin analogs. The model revealed at least three important sites for favorable electrostatic interactions and indicated favorable and unfavorable steric interaction sites. It was found that the occurrence of at least three positively charged and several hydrophobic amino acid residues is highly conserved at fixed positions of gp120 V3 loop sequences. This may support the validity of the proposed model and the hypothesis that porphyrins containing anionic and hydrophobic groups may interact with some of the highly conserved positively charged and hydrophobic sites, respectively, of the V3 loop. These interactions may induce conformational changes in the gp120 envelope glycoprotein leading to inhibition of virus entry into cells and of syncytium formation (cell-to-cell fusion) and thus to inhibition of virus replication.

Amino Acid Sequence↗

PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. The importance of the hydrophobic interaction in the mutagenicity of organic compounds.

The derivation of new QSAR and the review of published QSAR for the mutagenicity of a variety of chemicals acting on a variety of bacterial systems uncovers two classes of equations. 12 examples include a term for hydrophobicity and of these 12, 11 require activation either by S9 or cytosolic enzymes for the reduction of nitro compounds. There are 4 examples of direct-acting mutagens which do not require activation. Of these 4, 3 do not contain a term for hydrophobicity. The odd example is that of the sulfonate esters which do not require activation, but contain a term in log P. The hydrophobicity factor is not correlated with the type of bacteria used for the test.

Amines↗

PubMed1993

Mechanistic interpretation of the genotoxicity of nitrofurans (antibacterial agents) using quantitative structure-activity relationships and comparative molecular field analysis.

Quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) have been applied to elucidate the mechanisms of genotoxicity (SOSIP) of nitrofuran derivatives on Escherichia coli PQ37. The following equation was developed: log SOSIP = -33.1qc2 + 1.00 log P - 1.50Isat - 1.19MR - 0.76I5,6 - 3.76; n = 40, r = 0.900, s = 0.475. The QSAR model clearly reveals three important factors, namely, electronic (qc2), hydrophobic (log P) and steric (MR, Isat, I5,6) contributing toward the genotoxic activity of this class of compounds. qc2, the charge on the c2 atom attached to the NO2 group, supports a furan ring opening mechanism in explaining the genotoxicity. The finding of the coefficient of 1 with log P conforms to our previous findings with several different classes of mutagens acting on different systems. CoMFA analysis clearly demonstrates its potential in unraveling the steric features of the molecules through contour maps. The CoMFA cross-validated model also supports the importance of the electronic factor. It could not reveal any hydrophobic influence because the interaction energies of the CH3 and H2O probes are collinear. QSAR (classical) and CoMFA, if used judiciously, may complement each other and enhance the applicability of SAR in drug design.

Escherichia coli↗

PubMed1992

Mutagenic activity of a series of synthetic and naturally occurring heterocyclic amines in Salmonella.

26 synthetic and naturally occurring heterocyclic amines were tested in the Salmonella/microsome assay (Ames test) using tester strains TA98 and TA100 in the presence of an Aroclor-induced rat-liver S9 fraction. 9 of the compounds were protein-pyrolysis products which had previously been shown to be mutagenic. Mutagenic potencies similar to previously reported values were demonstrated for these compounds with the exception that Trp-P-1 was only mutagenic in strain TA98 in our study, although it had previously been reported to be weakly mutagenic in strain TA100. 17 structurally diverse heterocyclic amines were synthesized and tested for mutagenicity. The structural diversity of these synthetic heterocyclic amines will enhance the sensitivity of future quantitative structure-activity relationship (QSAR) studies by demonstrating the structural characteristics essential for mutagenicity. The results of this study provide a large data base for the mutagenicity of this important class of compounds.

Amines↗

PubMed1992

A QSAR investigation of the role of hydrophobicity in regulating mutagenicity in the Ames test: 1. Mutagenicity of aromatic and heteroaromatic amines in Salmonella typhimurium TA98 and TA100.

Quantitative structure-activity relationships (QSAR) have been derived for the mutagenic activity of 88 aromatic and heteroaromatic amines acting on Salmonella typhimurium TA98 + S9 and 67 amines acting on TA100 + S9. Mutagenic activity is linearly dependent on hydrophobicity, the energy of the highest occupied molecular orbital, and the energy of the lowest unoccupied molecular orbital of the amine. The dependence of mutagenic activity on hydrophobicity and electronic effects is nearly identical for TA98 and TA100. Mutagenic activity in TA98 is also found to depend on the size of the aromatic ring system. Different QSARs are derived for the mutagenic activity of hydrophilic amines (log P less than 1) acting on either TA98 or TA100. The mechanism of amine activation and reaction with DNA is considered in light of these findings.

Amines↗

PubMed1992

Quantitative structure-activity relationship investigation of the role of hydrophobicity in regulating mutagenicity in the Ames test: 2. Mutagenicity of aromatic and heteroaromatic nitro compounds in Salmonella Typhimurium TA100.

A quantitative structure-activity relationship (QSAR) has been derived for the mutagenic activity of 117 aromatic and heteroaromatic nitro compounds acting on Salmonella typhimurium TA100. Relative mutagenic activity is bilin-early dependent on hydrophobicity, with an optimal log P of 5.44, and is linearly dependent on the energy of the lowest unoccupied molecular orbital of the nitro compound. The dependence of mutagenic activity on hydrophobicity and electronic effects is very similar for TA98 and TA100. Mutagenic activity in TA100 does not depend on the size of the aromatic ring system, as its does in TA9. The effect of the choice of assay organism, TA98 versus TA100, on nitroarene QSAR is seen to be similar to the effect previously found for aminoarenes. Lateral verification of QSARs is presented as a tool for establishing the significance of a new QSAR.

Amines↗

PubMed1992

Structure-activity relationship of genotoxic polycyclic aromatic nitro compounds: further evidence for the importance of hydrophobicity and molecular orbital energies in genetic toxicity.

A quantitative structure-activity relationship (QSAR) has been formulated for 15 polycyclic aromatic nitro compounds acting on E. coli PQ37. Upon damage of DNA by these substances beta-galactosidase is induced and can be easily assayed colorimetrically, hence, this is a short-term test for mutagenicity. The QSAR (log SOSIP = 1.07 log P - 1.57 epsilon LUMO - 6.41) is strikingly similar to that found earlier with nitroaromatics acting in the Ames test (TA100) and differs significantly for that found using TA98 organisms. The QSAR brings out in a unique manner the underlying similarity in the two test systems.

Mutagenicity Tests↗

PubMed1992

Mutagenicity of quinolines in Salmonella typhimurium TA100. A QSAR study based on hydrophobicity and molecular orbital determinants.

The mutagenicity of 33 quinolines in the Salmonella test using TA98 and TA100 cells has been reported. Significant activity was found only with TA100 cells. Quantitative structure-activity relationships (QSAR) could be formulated using molecular orbital parameters or Hammett constants and hydrophobic parameters for those compounds with substituents in the 6, 7 and 8 positions. The QSAR points to the 2-position on the quinoline ring as being the site for activation by S9 oxidation.

Biotransformation↗

PubMed1991

Structure-activity relationship of mutagenic aromatic and heteroaromatic nitro compounds. Correlation with molecular orbital energies and hydrophobicity.

A review of the literature yielded data on over 200 aromatic and heteroaromatic nitro compounds tested for mutagenicity in the Ames test using S. typhimurium TA98. From the data, a quantitative structure-activity relationship (QSAR) has been derived for 188 congeners. The main determinants of mutagenicity are the hydrophobicity (modeled by octanol/water partition coefficients) and the energies of the lowest unoccupied molecular orbitals calculated using the AM1 method. It is also shown that chemicals possessing three or more fused rings possess much greater mutagenic potency than compounds with one or two fused rings. Since the QSAR is based on a very wide range in structural variation, aromatic rings from benzene to coronene are included as well as many different types of heterocycles, it is a significant step toward a predictive toxicology of value in the design of less mutagenic bioactive compounds.

Animals↗

PubMed1990

LUMO energies and hydrophobicity as determinants of mutagenicity by nitroaromatic compounds in Salmonella typhimurium.

Quantitative structure-activity relationships have been derived for the mutagenic activity of 47 nitroaromatic compounds acting on Salmonella typhimurium (TA100) and 66 acting on TA98. The mutagenicity is linearly dependent on the energy of the lowest occupied molecular orbital and bilinearly dependent on the hydrophobicity (octanol/water log P) of the mutagens. The mechanism of action is considered in the light of these findings.

Biotransformation↗