Computational Modelization of New HIV-1 Integrase Inhibitors | Poster Board #748

HIV-1 Integrase is an enzyme that plays an important role in the HIV DNA replication.
Allosteric HIV-1 Integrase Inhibitors (ALLINIs) create non-covalent interaction with the enzyme
with the purpose of disrupting the virus DNA replication. Compounds with structures capable of
forming covalent bonds with the integrase could enhance the potency of ALLINIs. KHP-1-482
has an epoxide group that undergo a ring-opening reaction to create covalent bonds with IN.
KHP-1-482 presents four different conformations capable of bonding covalently with the
integrase. Using computational modelizations to analyze the differences between these
conformations, it was found that KHP-1-482-B2 is the best candidate to create this covalent
bond. KHP-1-482-B2 is shown to have the lowest binding energy, meaning that it has more
affinity with IN. We also found a relationship between the distance between the epoxide from
KHP-1-482 and the Nitrogen residue of Lysine-173. The lowest the binding energy, the shortest
the distance. For the four different conformations, the distance was between 4.3 ~ 5.4 Å. Finally,
KHP-1-482 was compared to a carboxylic derivative under the same conditions. While the
carboxylic acid derivative proves to have a better binding affinity than KHP-1-482, it does not
generate a covalent bond. Even though the results are promising, more changes need to be made,
with the purpose to obtain better results.