Effect of hydroxyl group configuration in hydroxyethylamine dipeptide isosteres on HIV protease inhibition. Evidence for multiple binding modes

Rich, Daniel H.; Sun, Chong Qing; Prasad, J. V. N. Vara; Pathiasseril, Ahammadunny; Tóth, Máté; Marshall, Garland R.; Clare, Michael; Mueller, Richard A.; Houseman, Kathryn

doi:10.1021/jm00107a049

Cited by 141 publications

(63 citation statements)

References 3 publications

(5 reference statements)

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“…These two inhibitors share a transition state dipeptide ASN-PHE+(CH(OH)CH,N) and are expected to bind this portion of each inhibitor in a similar fashion. Because these inhibitors do not share chirality (JG-365 is an S-enantiomer and Ro-5989 is an R-enantiomer), it was speculated (Rich et al, 1991) that a binding mode allowing superposition of their hydroxyl groups would require local conformational rearrangements at another position in the inhibitor. These local rearrangements conserve the interaction with V32:CY through inhibitor contact with V:9:CY in the case of JG-365 and a tertiary-butyl group in the case of Ro-8959.…”

Section: Inhibitor Binding Modesmentioning

confidence: 99%

A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-1-protease inhibitor design

1995

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The interface between protein receptor-ligand complexes has been studied with respect to their binary interatomic interactions. Crystal structure data have been used to catalogue surfaces buried by atoms from each member of a bound complex and determine a statistical preference for pairs of amino-acid atoms. A simple free energy model of the receptor-ligand system is constructed from these atom-atom preferences and used to assess the energetic importance of interfacial interactions. The free energy approximation of binding strength in this model has a reliability of about * 1.5 kcal/mol, despite limited knowledge of the unbound states. The main utility of such a scheme lies in the identification of important stabilizing atomic interactions across the receptor-ligand interface. Thus, apart from an overall hydrophobic attraction (Young L, Jernigan RL, Covell DG, 1994, Protein Sci3:717-729), a rich variety of specific interactions is observed. An analysis of 10 HIV-1 protease inhibitor complexes is presented that reveals a common binding motif comprised of energetically important contacts with a rather limited set of atoms. Design improvements to existing HIV-1 protease inhibitors are explored based on a detailed analysis of this binding motif.

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Section: Inhibitor Binding Modesmentioning

confidence: 99%

A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-1-protease inhibitor design

1995

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“…Understandably, most authors approached the design of an HIV-I PR-specific inhibitor by replacing a scissile peptide bond of a proper peptide substrate by its noncleavable isostere, e.g. reduced bond [5], statine and its derivatives [B], hydroxyethylene [7], hydroxyethylamine [8,9] or difluoroketone and phosphinates [lo]. Alternative strategies, e.g.…”

Section: Introductionmentioning

confidence: 99%

Reduced‐bond tight‐binding inhibitors of HIV‐1 protease Fine tuning of the enzyme subsite specificity

et al. 1992

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Truncation of a peptide substrate in the N‐terminus and replacement of its scissile amide bond with a non‐cleavable reduced bond results in a potent inhibitor of HIV‐1 protease. A series of such inhibitors has been synthesized, and S2–S3′ subsites of the protease binding cleft mapped. The S2 pocket requires bulky Boc or PIV groups, large aromatic Phe residues are preferred in P1 and P′ and Glu in P2′. The S3′ pocket prefers Phe over small Ala or Val. Introduction of a Glu residue into the P2′ position yields a tight‐binding inhibitor or HIV‐1 protease, Boc‐Phe‐[CH2‐NH]‐Phe‐Glu‐Phe‐OMe, with a subnanomolar inhibition constant. The relevant peptide derived from the same amino acid sequence binds to the protease with a K i of 110 nM, thus still demonstrating a good fit of the amino acid residues into the protease binding pockets and also the importance of the flexibility of P1‐P1′ linkage for proper binding. A new type of peptide bond mimetic, N‐hydroxylamine ‐CH2‐N(OH)‐, has been synthesized. Binding of hydroxylamino inhibitor of HIV‐1 protease is further improved with respect to reduced‐bond inhibitor.

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“…For one of these complexes (ref. 6 and A. Wlodower, personal communication) and its analogs, binding constants are also available (8,9). This presents us with an opportunity to perform free-energy simulations that might aid in systematic design of peptide-based HIV-1-PR inhibitors.…”

mentioning

confidence: 99%

“…These three-dimensional structures were the starting points of the TCP calculations. Binding constants for this and a few other complexes have been measured experimentally (8,9). In the following sections, we first discuss the simulations involving the S configuration ofthe inhibitor (hydroxyethylene moiety).…”

mentioning

confidence: 99%

Relative differences in the binding free energies of human immunodeficiency virus 1 protease inhibitors: a thermodynamic cycle-perturbation approach.

Reddy

Viswanadhan

Weinstein

1991

Proc. Natl. Acad. Sci. U.S.A.

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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-LeuAsn-(Phe-Hea-Pro)-Ile-Val-OMe (S1) to Ac-Ser-Leu-Asn-(PheHea-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 K; 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.

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Effect of hydroxyl group configuration in hydroxyethylamine dipeptide isosteres on HIV protease inhibition. Evidence for multiple binding modes

Cited by 141 publications

References 3 publications

A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-1-protease inhibitor design

A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-1-protease inhibitor design

Reduced‐bond tight‐binding inhibitors of HIV‐1 protease Fine tuning of the enzyme subsite specificity

Relative differences in the binding free energies of human immunodeficiency virus 1 protease inhibitors: a thermodynamic cycle-perturbation approach.

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