Biomedical subjects

Mahindra T Makhija

Publications and source records attributed to Mahindra T Makhija.

5 recordsLinked to original sources

PubMed2006

Designing HIV integrase inhibitors--shooting the last arrow.

The arsenal of drugs in the fight against AIDS is rapidly diminishing as the HIV becomes resistant to the available reverse transcriptase and protease inhibitors. After killing millions all over the world, the virus is still on the rampage and hence the pharmaceutical industry is resorting to the development of inhibitors of integrase. This seems to be the last arrow in the quiver of potential drug leads to combat the deadly infection. Several classes of HIV integrase inhibitors have been reported to date; however, none is clinically useful. This review details the existing knowledge of the biological functions of the HIV-1 integrase with the focus on its available inhibitors, their disadvantages, and the current trends in designing novel compounds as anti-integrase.

Combinatorial Chemistry Techniques↗

PubMed2005

Correlation between inactive cathepsin D expression and retinal changes in mcd2/mcd2 transgenic mice.

PURPOSE: To investigate the correlation between the presence of the inactive cathepsin D (CatD) and retinal changes in mcd2/mcd2 transgenic mice. METHODS: Computational modeling was used to examine whether CatD mutants maintain competitive substrate binding. D407 cells were transfected with pcDNACatDM1 or pcDNACatDM2, containing procathepsin D (pro-CatD) with 6-bp (CatDM1) or 12-bp (CatDM2) deletions, respectively, flanking the pro-CatD cleavage site, and the aspartic protease activity of the transfected cells was measured. Subsequently, transgenic mice (mcd2/mcd2) containing CatDM2 were generated. Relative transgene copy number and transcript levels in the previously produced mcd/mcd (carrying CatDM1) and mcd2/mcd2 mice were measured by quantitative real-time PCR. Western blot analysis and aspartic protease activity were used to characterize the mutated proteins. Retinal changes were described by using color fundus photography and fluorescein angiography, histology, immunohistochemistry, and electron microscopy. RESULTS: Computational modeling of the CatDM1 and CatDM2 structures indicated that the substrate binding site was not altered. There was limited or no aspartic protease activity associated with CatDM1 and CatDM2 proteins, respectively. Mcd2/mcd2 animals contained a higher amount of inactive CatD than mcd/mcd or wild-type mice. Retinal abnormalities in mcd2/mcd2 mice developed at 3 months of age, earlier than in mcd/mcd mice. These changes included hypopigmentation, hyperfluorescence, retinal pigment epithelial (RPE) cell depigmentation or clumping, cell proliferation, and pleomorphism. Proliferating cells were identified as being of RPE origin. CONCLUSIONS: This study demonstrated a correlation between the presence of the inactive CatD in RPE cells and the development of ophthalmoscopic, cellular, and histologic changes in the retina.

Animals↗

PubMed2004

De novo design and synthesis of HIV-1 integrase inhibitors.

Existing AIDS therapies are out of reach for most HIV-infected people in developing countries and, where available, they are limited by their toxicity and their cost. New anti-HIV agents are needed urgently to combat emerging viral resistance and reduce the side effects associated with currently available drugs. Toward this end, LeapFrog, a de novo drug design program was used to design novel, potent, and selective inhibitors of HIV-1 integrase. The designed compounds were synthesized and tested for in vitro inhibition of HIV-1 integrase. Out of the 25 compounds that were designed, and synthesized, four molecules (compounds 23, 26, 43, and 59) showed moderate to low inhibition of HIV-1 integrase for 3'-processing and 3'-strand transfer activities. Nonetheless, these compounds possess structural features not seen in known HIV-1 integrase inhibitors and thus can serve as excellent leads for further optimization of anti-HIV-1 integrase activity.

HIV Integrase Inhibitors↗

PubMed2002

QSAR of HIV-1 integrase inhibitors by genetic function approximation method.

Quantitative structure--activity relationship (QSAR) paradigm, using genetic function approximation (GFA) technique was used to examine the correlations between the calculated physicochemical descriptors and the in vitro activities (3'-processing and 3'-strand transfer inhibition) of a series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors. Depending on the chemical structure, all molecules were divided into two classes---catechols and noncatechols. Eighty-one molecules were used in the present study and they were divided into training set and test set. The training set in each class consisted of 35 molecules and QSAR models were generated separately for both catechols and noncatechols. Equations were evaluated using internal as well as external test set predictions. Models generated for catechols show that electronic, shape related, and thermodynamic parameters are important whereas for noncatechols, spatial, structural, and thermodynamic properties play an important role for the activity.

Anti-HIV Agents↗

PubMed2002

3D-QSAR and molecular modeling of HIV-1 integrase inhibitors.

Three-dimensional quantitative structure-activity relationship (3D QSAR) methods were applied on a series of inhibitors of HIV-1 integrase with respect to their inhibition of 3'-processing and 3'-end joining steps in vitro. The training set consisted of 27 compounds belonging to the class of thiazolothiazepines. The predictive ability of each model was evaluated using test set I consisting of four thiazolothiazepines and test set II comprised of seven compounds belonging to an entirely different structural class of coumarins. Maximum Common Substructure (MCS) based method was used to align the molecules and this was compared with other known methods of alignment. Two methods of 3D QSAR: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were analyzed in terms of their predictive abilities. CoMSIA produced significantly better results for all correlations. The results indicate a strong correlation between the inhibitory activity of these compounds and the steric and electrostatic fields around them. CoMSIA models with considerable internal as well as external predictive ability were obtained. A poor correlation obtained with hydrophobic field indicates that the binding of thiazolothiazepines to HIV-1 integrase is mainly enthalpic in nature. Further the most active compound of the series was docked into the active site using the crystal structure of integrase. The binding site was formed by the amino acid residues 64-67, 116, 148, 151-152, 155-156, and 159. The comparison of coefficient contour maps with the steric and electrostatic properties of the receptor shows high level of compatibility.

Catalytic Domain↗