Attachment of envelope glycoprotein gp120 to the host cell receptor CD4 is the first step during the human immunodeficiency virus-1 (HIV-1) entry into the host cells that makes it a promising target for drug design. To elucidate the crucial three dimensional (3D) structural features of reported HIV-1 gp120 CD4 binding inhibitors, 3D pharmacophores were generated and receptor based approach was employed to quantify these structural features. A four-partial least square factor model with good statistics and predictive ability was generated for the dataset of 100 molecules. To further ascertain the structural requirement for gp120-CD4 binding inhibition, molecular interaction studies of inhibitors with gp120 was carried out by performing molecular docking using Glide 5.6. Based on these studies, structural requirements were drawn and new molecules were designed accordingly to yield new sulphonamides derivatives. A water based green synthetic approach was adopted to obtain these compounds which were evaluated for their HIV-1 gp120 CD4 binding inhibition. The newly synthesized compounds exhibited remarkable activity (10-fold increase) when compared with the standard BMS 806. Further the stability of newly synthesized derivatives with HIV-1 gp120 was also investigated through molecular dynamics simulation studies. This provides a proof of concept for molecular modeling based design of new inhibitors for inhibition of HIV-1 gp120 CD4 interaction.