Pentacycloundecane lactam vs lactone norstatine type HIV protease inhibitors: binding energy calculations and DFT study B.Honarparvar, H.G. Kruger, T.

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Pentacycloundecane lactam vs lactone norstatine type HIV protease inhibitors: binding energy calculations and DFT study B.Honarparvar, H.G. Kruger, T. Govender, G.E. M. Maguire Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, South Africa December 2013

Structures of PCU-lactam-EAIS, its tautomer PCU-lactim- EAIS, PCU-lactone-EAIS inhibitors and PCU-models

 MD simulation  Binding free energy calculations  DFT study Objectives

Software: Amber12 Method: MMPB(GB)SA Binding free energy calculations

PCU- peptide inhibitor inside the active site of South African HIV protease

PCU-peptide inhibitor docked to HIV protease

The MM-PB(GB)SA method can be conceptually summarized as: ΔG bind = G complex – (G enzyme + G ligand ) where G complex, G enzyme and G ligand are the free energies of the complex, the enzyme and the ligand, respectively. MM-PB(GB)SA binding free energy calculations

Binding free energies and its components for the PCU-models complexed with the HIV protease PCU-modelsΔE ELE ΔE VDW ΔE SOL ( PB) ΔE SOL (G B) ΔG bind (PB SA) ΔG bind (GBS A) PCU-lactam(a) PCU-lactam(b) PCU-lactim(a) PCU-lactim(b) PCU-lactone(a) PCU-lactone(b)

Binding free energies and its components for the PCU-peptides complexed with the HIV protease PCU-peptidesΔE ELE ΔE VDW ΔE SOL ( PB) ΔE SOL (G B) ΔG bind (PB SA) ΔG bind (G BSA) PCU-lactam-NH-EAIS(a) PCU-lactam-NH-EAIS(b) PCU-lactim-NH-EAIS(a) PCU-lactim-NH-EAIS(b) PCU-lactone-CO-EAIS(a) PCU-lactone-CO-EAIS(b)

Binding free energies and its components for the synthesized PCU-peptides complexed with the HIV protease PCU-peptidesΔE ELE ΔE VDW ΔE SOL ( PB) ΔE SOL (G B) ΔG bind (P BSA) ΔG bind ( GBSA) PCU-lactam-CO-EAIS(a) PCU-lactam-CO-EAIS(b) PCU-lactim-CO-EAIS(a) PCU-lactim-CO-EAIS(b) PCU-lactone-NH-EAIS(a) PCU-lactone-NH-EAIS(b)

Software: Gaussian09 Method: B3LYP Basis set: 6-311G** DFT study of PCU-models

Electronic structure properties  NBO Analysis Polarizability Electrostatic Potential Map  (HOMO- LUMO) Natural atomic charges

Natural atomic charges (a.u.) on nitrogen and oxygen nuclei of PCU-models AtomLactam Lactim Lactone N 1 /O O2O O3O N4N O5O

Electrostatic Potential Map PCU-lactim PCU-lactam PCU-lactone

The frontiers orbitals of PCU-models (a) HOMO for Lactam (b) LUMO for Lactam (a) HOMO for Lactim (b) LUMO for Lactim (a) HOMO for Lactone (b) LUMO for Lactone

Polarizability (Å 3 ), dipole moment (Debye) and Gibbs free solvation energy ∆G solv (kcal/mol) values of the PCU-models PCU-modelsα (Å 3 )µ (Debye) ∆G Solv (kcal/mol) PCU-lactam PCU-lactim PCU-lactone

Acknowledgements We thank the National Research Foundation for financial support, UKZN, and the CHPC ( for computational resources.

Thank you for your kind attention