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Full quantum mechanical study of binding of HIV‐1 protease drugs
Author(s) -
Zhang Da W.,
Zhang John Z. H.
Publication year - 2005
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.20488
Subject(s) - amprenavir , saquinavir , indinavir , hiv 1 protease , protease , nelfinavir , chemistry , hydrogen bond , lopinavir , stereochemistry , computational chemistry , human immunodeficiency virus (hiv) , biochemistry , enzyme , organic chemistry , virology , biology , molecule , sida , antiretroviral therapy , viral load , viral disease
Fully quantum mechanical studies of detailed binding interactions between HIV‐1 protease and six FDA (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. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005