The functional dynamic assembly of integration complex with chromatin remains unclear due to multiple protein-protein and protein-DNA bounds engaged in the intasome-nucleosome complex making difficult to monitor this process. In order to investigate this mechanism, and provide new tools to dissect the process, we developed an alphascreen approach using PFV intasome and the human nucleosome. This model has been used to select compounds able to modulate the interactions engaged in the intasome/nucleosome complex. Molecular studies led us to identify small molecules able to disrupt the intasome-nucleosome complex by acting either on the DNA topology within the nucleosome or on the IN/histone tail interactions. Both biochemical and cellular experiments allowed us especially to identify new histone binder drugs able to inhibit retroviral integration both in PFV and HIV-1 model. In addition to provide new information about the intasome-nucleosome interactions determinants our work also provides new compounds constituting molecular tools that can be used for studying further the functional IN/nucleosome interactions. Our results pave now the way to further fundamental studies and large scale screening of drugs targeting specifically this functional nucleocomplex or additional nucleosome-partner complexes.