HIV-1 attachment, despite being an ideal target stage to stop infection from the beginning, remains as one of the HIV lifecycle phases with less amount of designed and commercially . CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/330142 doi: bioRxiv preprint first posted online May. 24, 2018; 2 available inhibitors. To contribute to the urgently needed discovery of new active compounds that could become part of the current highly active antiretroviral therapy, and as an attempt to explore a massive chemical space, high-throughput virtual screening of 16.3 million combinatorially generated and piperazine-cored compounds, was accomplished. Docking calculations, molecular dynamics simulations, and QSAR analyses were carried out to assess the suitability of each ligand to bind gp120 envelope glycoprotein, thus preventing it from binding to CD4 co-receptor. Ligand 255 stands out as a promising candidate to be tested beyond computational methodologies, and the 4,5,6,7-tetrahydroindole fragment is reported as a better group to bind inside the Phe43 cavity than the substituted indoles reported in the literature.