In this study, all-atom unrestrained 500ns long MD simulations of the CD4-HT1 protein complex in an aqueous solutions were performed to explore the dynamics of the protein and also to predict the ligands that the bind and potentially inhibit the CD4-HT1 complex formation. Rootmean-square deviations (RMSDs) of the complexes were used to quantify the structural changes in the protein-ligands complex. The RMSD value remained below 1.5A. Based on our MD simulations, in the CD4-HT1 complex the CD4 binding region on the HT1 protein is partially negative as shown in electrostatic surface potential in Figure . To complement this binding region the CD4 binding region is mostly positive. This shows the strong binding of these two proteins. The HT1 proteins contains a unique cavity known as Phe43 cavity since the cavity accommodates the Phe43 amino acids and is considered as a crucial in the two-protein binding and HIV infection. Therefore, the current strategy is to binding a small molecular to this biding site and hence the interaction of these two proteins can be prevented. The protein-ligand interactions were calculated by Protein-Ligand Interaction Profiler (PLIP) web server as shown in Table . The Ligand I form interaction with the protein by forming hydrophobic interactions with Thr257, Glu370, Glu370, and Trp427 residues with distance of 3.81, 3.53, 3.45, and 3.40 Å respectively. In addition, it forms two hydrogen bonds with Asn425 at a distance of 2.49 and 2.17 Å, respectively. In this complex Ligand II interactions with the protein by forming hydrophobic interactions with Val255, Thr257, Glu370, and Glu370 at 3.67, 3.64, 3.58, and 3.30Å, respectively. Moreover, it forms one π-Stacking with Trp427 at 4.62Å. The Ligand III formed five hydrophobic interactions with Val255 (3.94Å), Thr257 (3.80Å), Glu370 (3.61 and 3.35Å), and Trp427 (2.64Å). In addition, it formed two hydrogen bonds with Glu370 and Asn425 at a distance of 2.64 and 2.64Å, respectively. The Ligand IV formed only one hydrophobic interaction with Val371 (3.54Å) and three hydrogen bonds with Ser365, Thr455, Asp457 at a distance of 2.05, 2.06, and 1.85Å, respectively. Finally, Ligand V formed eight hydrophobic interactions with Residue Val255, Thr257, Asp368, Glu370, Glu370, Val371, and Trp427 at a distance of 3.54, 3.68, 3.71, 3.47, 3.85, 3.83, and 3.67Å, respectively. Moreover, it formed two hydrogen bonds with Asn425 (2.71 and 1.83Å) and one π-Stacking with Trp427 (4.53Å). Interestingly, all these ligands bind to the cavity present in the protein called as Phe43 cavity as shown in Figure . This cavity has been suggested as a useful target for antiviral strategies. Previous studies have revealed that the HIV entry can be inhibited by filling the Phe43 cavity. To evaluate the pharmaceutical properties of the proposed ligands we have performed absorption, distribution, metabolism, and excretion evaluation of the ligands by using SwissADME web server. Based on this study, ligands have high gastro intestinal (GI) absorption and high blood brain barrier (BBB) permutation (Table ). In addition, all the ligand passed Lipinski rule hence they all show high drug likeliness. Further analysis is required to find the effect of these ligands on the structure of the protein. This will be done by performing molecular dynamics simulation studies in future studies. Molecular dynamics simulations were also performed starting from the molecular docking poses for the complexes of 5 high-interest compounds using the GROMACS software. In all MD simulations the ligands bind strongly to the binding site.