Binding Free Energy Calculations of Nine FDA‐approved Protease Inhibitors Against HIV‐1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

Abstract

In this work, have investigated the binding affinities of nine FDA-approved protease inhibitor drugs against a new HIV-1 subtype C mutated protease, I36T↑T. Without an X-ray crystal structure, homology modelling was used to generate a three-dimensional model of the protease. This and the inhibitor models were employed to generate the inhibitor/I36T↑T complexes, with the relative positions of the inhibitors being superimposed and aligned using the X-ray crystal structures of the inhibitors/HIV-1 subtype B complexes as a reference. Molecular dynamics simulations were carried out on the complexes to calculate the average binding free energies for each inhibitor using the molecular mechanics generalized Born surface area (MM-GBSA) method. When compared to the binding free energies of the HIV-1 subtype B and subtype C proteases (calculated previously by our group using the same method), it was clear that the I36T↑T proteases mutations and insertion had a significant negative effect on the binding energies of the non-pepditic inhibitors nelfinavir, darunavir and tipranavir. On the other hand, ritonavir, amprenavir and indinavir show improved calculated binding energies in comparison with the corresponding data for wild-type C-SA protease. The computational model used in this study can be used to investigate new mutations of the HIV protease and help in establishing effective HIV drug regimes and may also aid in future protease drug design.

Evaluating the Performance of a Non-Bonded Cu2+ Model Including Jahn−Teller Effect into the Binding of Tyrosinase Inhibitors

“…Therefore, the development of TYR inhibitors with efficient bioactivity and less toxicity is a relevant branch of scientific research. Recently, we have used molecular modeling approaches to investigate biomolecular systems with an emphasis on enzymatic reactions and inhibition [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

Exploring the flap dynamics of the South African HIV subtype C protease in presence of FDA‐approved inhibitors: MD study

“…The PDB entries are as follows: 3UL1 (apo/free), 3EL1 (ATV), 4DQB (DRV), 1MUI (LPV) and 2O4P (TPV) while the PDB entry for the natural substrate is 1KJH. The C‐SA/inhibitor complexes were prepared as described previously …”

“…Acquired Immunodeficiency Syndrome (AIDS) is regarded as one of the most devastating disease outbreaks to date . Human Immunodeficiency Virus (HIV) is the causative agent for AIDS and approximately 36.7 million people were reported to be suffering from AIDS at the end of 2016 .…”

“…HIV‐1 protease is generally a homodimer with two identical monomers (chain A and chain B) each consisting of 99 amino acids . However, our group recently reported 100 and 101 amino acid mutant variants of C‐SA protease that demonstrated little difference in catalytic activity with respect to the natural substrate . The first mutant has one extra amino acid (I36T↑T) and the second mutant has two additional amino acids (E35D↑G↑S) in each monomer .…”

“…We have previously reported the theoretical binding affinity of nine FDA approved protease inhibitors (PIs) [amprenavir (APV), atazanavir (ATV), darunavir (DRV), indinavir (INV), lopinavir (LPV), nelfinavir (NFV), ritonavir (RTV), saquanavir (SQV) and tipranavir (TPV)] with subtype B and C‐SA on the basis of 2 ns molecular dynamics simulations . In addition, we separately reported the theoretical binding affinities of these FDA approved drugs against I36T↑T mutation of subtype C‐SA . Recently, our group determined the experimental binding affinities of these nine FDA approved drugs against C‐SA PR and the mutant (I36T↑T) .…”