Molecular docking studies on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepinone (TIBO) derivatives as HIV-1 NNRT inhibitors

Abstract

At present, chemotherapy seems to be the main weapon in the arsenal of remedies for the ongoing crusade against AIDS. The mode of binding of the TIBO family of inhibitors has been of interest because these compounds do not fit the two-hinged-ring model as generally observed in the NNRTIs. Flexible docking simulations were performed with a series of 53 TIBO derivatives as NNRTIs. Binding preferences as well as the structural and energetic factors associated with them were studied. A good correlation (r(2)=0.849, q(2)=0.843) was observed between the biological activity and binding affinity of the compounds which suggest that the identified binding conformations of these inhibitors are reliable. Further screening of PubChem database yielded novel scaffolds. Our studies suggest that modifications to the TIBO group of inhibitors might enhance their binding efficacy and hence, potentially, their therapeutic utility.

A group center overlap based approach for “3D QSAR” studies on TIBO derivatives

“…These scaffolds can serve as precursors for design and synthesis of newer and novel NNRTIs against HIV-1 RT. When comparing the results with our earlier work, 24 wherein we have used the same external dataset, it is found that the some of the common hits obtained earlier as well as in the present case has nearly the same binding affinities, which suggest the robustness of the method and model presented here.…”

“…PubChem compound database 24 (http://pubchem.ncbi.nlm.nih.-gov), containing more than 10 million compounds, used earlier was considered for virtual-screening using the best of the MLR as well as the ANN model, so as to retrieve putative hits. A search based on similar structure with compound similarity !90% followed by screening using Lipinsky's rule and presence of unfavorable functional groups yielded a subset of 128 compounds.…”

“…Thus 27 compounds were selected with activity higher than 6.5. These compounds were then docked into 1REV (The docking algorithm used yielded redocked RMSD 5 0.269 Å and E binding 5 225.86 kJ/mol) 24 and their respective binding affinities were evaluated. Table 6 presents the predicted activities (pIC 50 ) of the selected 27 compounds along with their binding affinities in kJ/mol (Fig.…”

“…[19][20][21] Comparison of the different RT-NNI complexes suggest modifications to the TIBO group of inhibitors, which might enhance their binding and hence, potentially, their therapeutic efficacy. [22][23][24] Tivirapine, one of the earliest NNRTI, to enter into the clinical trials, is a TIBO derivative. 25 In fact, QSAR as a technique attempts to summarize chemical and biological information to generate relationships between the structure and biological activity, hastens the drug design and aims to develop these compounds.…”

Computational modeling studies on anti-HIV-1 non-nucleoside reverse transcriptase inhibition by dihydroalkoxybenzyloxopyrimidines analogues: an electrotopological atomistic approach

“…[18] Since then three more NNRTIs-nevirapine, delavirdine and efavirenz have been approved for the treatment of HIV-1 and a few more are in clinical development, including rilpivirine, etravirine and dapivirine [19]. Till date various molecular modelling studies have been performed using QSAR [20], QSPR [21], Simple docking [22] and Template docking [23] on some NNRTIs.…”