Computational design of norbornane-based HIV-1 protease inhibitors

Dawei Zhang, Liu Ze Yu, Philip Lin Huang, Sylvia Lee-Huang, John Z.H. Zhang

Research output: Contribution to journalArticle

Abstract

A series of norbornane-based HIV-1 protease (PR) inhibitors are designed theoretically to displace the tetrahedrally coordinated internal water molecule that bridges inhibitor to flaps via hydrogen bonds. These designed inhibitors use the norbornenone oxygen atom to mimic this structural water molecule and contain diols to interact with the carboxylate oxygens of catalytic aspartates. The binding free energies were estimated by modified linear interaction energy approach [Zoete H, Michielin O, Karplus M, J Comput Aided Mol Des 17:861, 2003], in which the binding free energy is written as a linear combination of the electrostatic interaction energy between PR and the ligand, Eelec, the van der Waals interaction energy between PR and the ligand, EvdW, and the difference of the solvation free energies of the complex, the receptor, and the isolated ligand, ΔGsolv. The equation obtained in previous work [Da W. Zhang, Philip Lin Huang, Sylvia Lee-Huang, John Z. H. Zhang, J Theor Comput Chem 7:485, 2008] is applied directly to calculate the binding free energy of designed norbornane-based HIV-1 PR inhibitors.

Original languageEnglish (US)
Pages (from-to)471-485
Number of pages15
JournalJournal of Theoretical and Computational Chemistry
Volume9
Issue number2
DOIs
StatePublished - Apr 1 2010

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Keywords

  • HIV-1 protease
  • linear interaction energy
  • norbornane-based inhibitor

ASJC Scopus subject areas

  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Computational Theory and Mathematics

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