Abstract
Background: High attrition rate in late drug discovery and development stages leads to financial loss to industries and Governments. Despite the global prevalence of HIV infection and lack of promising treatment for AIDS patients, there are only a few drugs approved for the management of infected patients. There is an urgent need to discover newer anti-HIV drugs with novel mechanism of action and with efforts to reduce attrition rate in early drug discovery stages.
Objective: Prioritization of reported potential anti-HIV-1 leads according to their quantitative estimation of druglikeness (QED), carcinogenicity, mutagenicity, absorption, metabolism and toxic properties. Synthesis of analogs of the best lead and evaluation of their anti-HIV-1 activity is shown.
Methods: In silico anti-HIV lead prioritization was performed on a set of known anti-HIV natural products in order to obtain a lead with better druglikeness and ADMET properties. Prioritized lead tembamide and its four analogs were synthesized and their anti-HIV-1 activity was evaluated.
Results: Tembamide was found to be a lead with better QED, absorption and metabolism properties and with no carcinogenicity, mutagenicity and toxic potential. (+)-Tembamide is previously reported to show potent anti-HIV-1 activity against laboratory adapted strains HIV-1IIIB (X4, subtype B) and HIV-1Ada5 (R5, subtype B) in H9 cell line. It was observed during this study that synthesized tembamide and its four analogs were weakly active against primary isolates HIV-1UG070 (X4, subtype D) and HIV-1VB59 (R5, subtype C) in TZM-bl cell line.
Conclusion: The results showed that there is scope for the improvement of activity of tembamide analogs to discover a potent anti-HIV compound.
Keywords: QED, tembamide, anti-HIV, drugikeness, admetSAR, VirtualToxLab.
Graphical Abstract
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