Linked Life Data

1946447

Source:http://linkedlifedata.com/resource/pubmed/id/1946447

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
22
pubmed:dateCreated
1991-12-26
pubmed:abstractText
Peptidomimetic inhibitors of the human immunodeficiency virus 1 protease show considerable promise for treatment of AIDS. We have, therefore, been seeking computer-assisted drug design methods to aid in the systematic design of such inhibitors from a lead compound. Here we report thermodynamic cycle-perturbation calculations (using molecular dynamics simulations) to compute the relative difference in free energy of binding that results when one entire residue (valine) is deleted from one such inhibitor. In particular, we studied the "alchemic" mutation of the inhibitor Ac-Ser-Leu-Asn-(Phe-Hea-Pro)-Ile-Val-OMe (S1) to Ac-Ser-Leu-Asn-(Phe-Hea-Pro)-Ile-OMe (S2), where Hea is hydroxyethylamine, in two different (R and S) diastereomeric configurations of the hydroxyethylene group. The calculated (averaged for R and S) difference in binding free energy [3.3 +/- 1.1 kcal/mol (mean +/- SD); 1 cal = 4.184 J] is in good agreement with the experimental value of 3.8 +/- 1.3 kcal/mol, obtained from the measured Ki values for an equilibrium mixture of R and S configurations. Precise testing of our predictions will be possible when binding data become available for the two disastereomers separately. The observed binding preference for S1 is explained by the stronger ligand-protein interaction, which dominates an opposing contribution arising from the large desolvation penalty of S1 relative to S2. This calculation suggests that the thermodynamic cycle-perturbation approach can be useful even when a relatively large change in the ligand is simulated and supports the use of the thermodynamic cycle-perturbation algorithm for screening proposed derivatives of a lead inhibitor/drug prior to their synthesis.
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2002464, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2163604, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2184237, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2194475, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2200122, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2247458, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2330368, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2475171, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2548279, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2645523, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2660832, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2686029, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-2727695, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-3200837, http://linkedlifedata.com/resource/pubmed/commentcorrection/1946447-7213619
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0027-8424
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
88
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
10287-91
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed:year
1991
pubmed:articleTitle
Relative differences in the binding free energies of human immunodeficiency virus 1 protease inhibitors: a thermodynamic cycle-perturbation approach.
pubmed:affiliation
Agouron Pharmaceuticals, Inc., San Diego, CA 92121.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S.