Abstract
Nelfinavir (Viracept®, Pfizer), and Amprenavir (Ageneraze®, GlaxoSmithKline) are potent bioavailable inhibitors of the enzyme Protease (PR) of the Human Immunodeficiency Vírus-1 (HIV-1), which have been developed by consistent structure-based drug design projects, and have been approved worldwide for the treatment of HIV infected patients. They act as competitive inhibitors, and tightly bind the active site of PR with high shape and electrostatic potential complementarity. However, the virus has shown the ability of fixating mutations which decrease the affinity of the antiretrovirals for the binding pocket of PR, although at the cost of decreasing (but to a minor extent) the affinity for the substrate. The consequent appearance of drug resistance compromised the long term efficacy of the drug. In this work we have extended such structure based drug design effort with computational methodologies, by performing very small substitutions in the inhibitors, directed at interacting with the most conserved amino acids. It is not possible to mutate the latter, at the cost of making the enzyme catalytically inactive. We show with a set of examples that significant increases in affinity can still be achieved without changing the overall structure, molecular mass and hydrophobicity of the inhibitors, thus preserving their very favourable ADME properties.
Keywords: relative binding energy, Binding Free Energy, rg87-inhibitors, Nelfinavir, hydrogen bond donor
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