3-DIMENSIONAL STRUCTURE-ACTIVITY ANALYSIS OF A SERIES OF PORPHYRIN DERIVATIVES WITH ANTI-HIV-1 ACTIVITY TARGETED TO THE V3 LOOP OF THE GP120 ENVELOPE GLYCOPROTEIN OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

Using comparative molecular field analysis (CoMFA), a 3D-QSAR model wa s developed for 21 porphyrin derivatives which have anti-HIV-l activit y and bind to the V3 loop of the envelope glycoprotein gp120 of the hu man immunodeficiency virus type 1. A significant PLS cross-validated r (cv)(2) (0.590) was obtained, indicating that the model could be used as a predictive tool for further design of porphyrin analogs. The mode l revealed at least three important sites for favorable electrostatic interactions and indicated favorable and unfavorable steric interactio n sites. It was found that the occurrence of at least three positively charged and several hydrophobic amino acid residues is highly conserv ed at fixed positions of gp120 V3 loop sequences. This may support the validity of the proposed model and the hypothesis that porphyrins con taining anionic and hydrophobic groups may interact with some of the h ighly conserved positively charged and hydrophobic sites, respectively , of the V3 loop. These interactions may induce conformational changes in the gp120 envelope glycoprotein leading to inhibition of virus ent ry into cells and of syncytium formation (cell-to-cell fusion) and thu s to inhibition of virus replication.