HIV-1 drug resistance due to mutations in the active and inactive site is a major problem encountered in currently available anti-HIV treatments which need to design drugs that are active against the virus. In order to identify selective and potent compounds, we successfully constructed common pharmacophore hypothesis using clinically used ten drug molecules followed by in silico virtual screening, ADME, MMGBSA, IFD and molecular dynamics simulation that can inhibit WT as well as four MTs HIV-1 PR (I54M, V82T, I84V and L90M). The pharmacophore model AAAHR was generated and validated through enrichment calculation. The validated model was used as a query to retrieve novel and potential compounds from six databases. The screened compounds were subjected to ADME filtration to find the drug-like compounds followed by hierarchal multistage virtual screening to get common compounds that inhibit WT and four MTs HIV-1 PR. The hits retrieved at the end of screening displayed six common compounds present in all five proteins. Based on the docking score and binding energy, the three compounds were chosen which were interacting with most of the conserved active site amino acids of protease. In particular, ZINC12866729 interacted by making salt bridges with, D29/29′ and D30/30′ of WT and MTs HIV-1 PR. The results displayed that NCI-524545 had shown good interactions with WT as well as four MTs HIV-1 PR in comparison to DRV and LPV. In most of the mutations, DRV and LPV somewhat lost their interaction with the protein throughout the simulation, whereas NCI-524545 and ZINC12866729 retained interactions with the WT and mutated proteases. The importance of the water molecules for the interactions confirmed that these are needed for the hydrogen bonding interactions between I50, I50′ and compounds as well as with protein to maintain the stable conformations of the protein-ligand complex. Furthermore, hydrophobic amino acid residues of all proteins had shown an important role in the ligand binding by involving in hydrophobic contact with these two compounds. This approach has delivered two lead molecules which can inhibit both WT as well as four MTs HIV-1 PR. This two lead molecules can be validated through wet lab techniques to conform the activity.