We present an approach for designing new inhibitors (I) of HIV-1 aspartic protease (PR) based on calculation of relative binding energies, taking into account contributions from all species involved in the complexation equilibrium (I + PR ⇔ I:PR), as well as their solvation. This allows a rational design of new structures with predicted enhanced inhibitory potency. We have also analysed the role in binding affinity of the central non-scissile bond (X1-X2) as well as of flanking amino acid residues Pn of inhibitor structures (P3-P2-P1-X1-X2-P1′-P2′-P3′).
