Full quantum mechanical study of binding of HIV-1 protease drugs

D. A W Zhang, John Zhang

Research output: Contribution to journalArticle

Abstract

Fully quantum mechanical studies of detailed binding interactions between HIV-1 protease and six PDA (Food and Drug Administration)-approved drugs (saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, and lopinavir) are carried out using a recently developed MFCC (molecular fractionation with conjugate caps) method. The MFCC calculation produces a quantum mechanical interaction spectrum for any protease drug binding complex. Detailed quantitative analysis on binding of lopinavir to specific residues of the protease is given from the current study. The present calculation shows that the dominant binding of lopinavir to the protease is through the formation of a strong hydrogen bond between the central hydroxyl group of the drug to the aspartate oxygen of Asp25 in one of the two chains of the protease (A chain). This is closely followed by hydrogen binding of the drug to Asp29 in the B chain and somewhat weak hydrogen bonding to Asp30, Gly27, Gly48, and Ile50 in both chains. By partitioning all six drugs into four building blocks besides the central component containing the hydroxyl group, MFCC calculation finds that block III has essentially no binding interaction with the protease and the major binding interactions of these drugs are from blocks II and IV, in addition to the dominant central hydroxyl group. This detailed quantitative information on drug binding to the protease is very useful in rational design of new and improved inhibitors of HIV-1 protease and its mutants.

Original languageEnglish (US)
Pages (from-to)246-257
Number of pages12
JournalInternational Journal of Quantum Chemistry
Volume103
Issue number3
DOIs
StatePublished - Jun 5 2005

Fingerprint

protease
human immunodeficiency virus
drugs
Peptide Hydrolases
Lopinavir
Pharmaceutical Preparations
Fractionation
Hydroxyl Radical
caps
fractionation
Hydrogen bonds
Nelfinavir
Saquinavir
Indinavir
Ritonavir
interactions
aspartates
Personal digital assistants
Human immunodeficiency virus 1 p16 protease
Aspartic Acid

Keywords

  • ab initio
  • HIV-1 protease
  • MFCC

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry

Cite this

Full quantum mechanical study of binding of HIV-1 protease drugs. / Zhang, D. A W; Zhang, John.

In: International Journal of Quantum Chemistry, Vol. 103, No. 3, 05.06.2005, p. 246-257.

Research output: Contribution to journalArticle

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