Investigation of novel indole-based HIV-1 protease inhibitors using virtual screening and text mining

Human immunodeficiency virus type 1 protease (HIV-1 PR) inhibitors have been used as possible therapeutic agents for HIV-1 infection in clinical study. Most of the HIV therapy-related problems usually stem from long-term opioid usage. The rapid development of drug-resistant variants limits the long-term effectiveness of current inhibitors as therapeutic agents. In addition, different side effects were reported. Further drug development is required to design new compounds which have similar efficacy as the drugs currently used in HIV infection but without having undesirable side effects. Indole derivatives were considered as one of the effective HIV inhibitors. Indole is an important fragment used in many FDAapproved medicines and used in various diseases. For this purpose, in this study the molecules containing indole keywords in their fragments are taken from the Specs-SC database which includes 212520 small molecules. 5194 molecules that include indole keywords are selected. These selected molecules are then screened against HIV-1 PR target protein using molecular docking simulations. Then the molecules are ranked according to the their docking scores. Top docking poses of ten ligands and FDA approved drug Amprenavir are subjected to 100 ns Molecular Dynamics (MD) simulations. Thus, by using combination of text mining and integrated molecular modeling approaches, we identified novel indole-based hits against HIV-1 PR. Communicated by Ramaswamy H. Sarma

Automated summary

In this study, novel indole-based hits against HIV-1 PR were identified by screening molecules containing indole keywords, and using a combination of molecular docking and molecular dynamics simulations.