title: 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.
authors.affiliation: Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Husain A
authors.initials: HA
authors.lastname: Lockhat
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, Belém, PA, 66075-110, Brazil.
authors.forename: José R A
authors.initials: JR
authors.lastname: Silva
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, Belém, PA, 66075-110, Brazil.
authors.forename: Cláudio N
authors.initials: CN
authors.lastname: Alves
authors.affiliation: Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Thavendran
authors.initials: T
authors.lastname: Govender
authors.affiliation: Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 11101, Belém, PA, 66075-110, Brazil.
authors.forename: Jerônimo
authors.initials: J
authors.lastname: Lameira
authors.affiliation: Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.|School of Chemistry and Physics, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Glenn E M
authors.initials: GE
authors.lastname: Maguire
authors.affiliation: Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Wits, 2050, South Africa.
authors.forename: Yasien
authors.initials: Y
authors.lastname: Sayed
authors.affiliation: Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D017386:Sequence Homology, Amino Acid; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000596:Amino Acids; D017320:HIV Protease Inhibitors
keywords: 100 amino acids; C-SA HIV PR; I36T↑T; insertion; mutation