The HIV/AIDS poses to be a destructive pandemic to humans worldwide. microbicides play an important role in controlling HIV. Microbicides are self- administered prophylactic agents that impede transmission of HIV. Microbicides are products designed to be applied to the vagina or rectum for the purpose of reducing the acquisition of STI’s including HIV . Antiretroviral (ARV) drugs act at different stages of HIV life cycle, hindering the process of HIV infection and replication. ARV drugs that specifically target HIV include nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and Entry inhibitors. The present study focuses on entry inhibitors because they target the viral life cycle at an initial stage of infection itself.Homology modeling was used to build 3D models of CXCR4 receptor. The resultant models were subjected to structure validation and they were found to be satisfactory. Protein-ligand interactions were carried out to predict the binding conformations of various CXCR4 antagonists with their respective receptors which is an essential factor for designing new drugs. Out of 114 antagonists selected, about five antagonists showing best Glide scores were shortlisted. The predicted ligand-receptor interaction models provided a satisfactory explanation for the binding between the receptor and the corresponding ligands. The entry inhibitors can be considered as potential microbicides which can be subjected to in vitro and in vivo studies to decide the efficacy and the formulation in which it has to be developed.Entry inhibitors act very early in the HIV life cycle long before integration occurs. HIV infects a cell by binding to CD4 receptor of the target cell membrane. In addition to binding to CD4, HIV must also bind with a co-receptor ie. Chemokine receptors CCR5 and CXCR4 expressed on the cell membrane to enter a T cell.