Binding of the Second Generation Non-nucleoside Inhibitor S-1153 to HIV-1 Reverse Transcriptase Involves Extensive Main Chain Hydrogen Bonding

Ren, Jingshan; Nichols, C.E.; Bird, Louise E.; Fujiwara, Tamio; Sugimoto, H.; Stuart, David I.; Stammers, D.K.

doi:10.1074/jbc.275.19.14316

Cited by 130 publications

(112 citation statements)

References 30 publications

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“…One approach to the design of 'mutation resistant' inhibitors has consisted of the design of ligands making extensive main chain hydrogen bonding contacts with the enzyme [18].…”

Section: Rtmentioning

confidence: 99%

Combining structure-based drug design and pharmacophores

Griffith

Luu

Keller

2005

Journal of Molecular Graphics and Modelling

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Development towards integrated computer-aided drug design methodologies is presented by utilising crystal structure complexes to produce structure-based pharmacophores. These novel pharmacophores represent the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The protein-ligand complexes can also yield information about all interactions that ligands could potentially form with the binding site, as well as about the size of the binding cavity. Together, these describe a 'superligand', which can also be viewed as a pharmacophore. Various types of novel pharmacophores are discussed and compared, using HIV-1 Reverse Transcriptase (RT) as the target protein, and their application in database searching is presented. KeywordsDrug design, ligand-based pharmacophore, structure-based pharmacophore, novel pharmacophores, database searching KeywordsDrug design, ligand-based pharmacophore, structure-based pharmacophore, novel pharmacophores, database searching.

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“…One approach to the design of 'mutation resistant' inhibitors has consisted of the design of ligands making extensive main chain hydrogen bonding contacts with the enzyme [18].…”

Section: Rtmentioning

confidence: 99%

Combining structure-based drug design and pharmacophores

Griffith

Luu

Keller

2005

Journal of Molecular Graphics and Modelling

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“…The so-called Ôsecond generationÕ NNRTIs such as Efavirenz (DMP-266) [9], carboxanilides [10], PETT analogues [11] and the recent member S-1153 [12] demonstrate more favorable resistance profiles. Efforts are now being put on the design of new inhibitors with improved resistance profiles to the most frequently drug-induced mutations generated within RT.…”

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confidence: 99%

Structural basis for the inhibitory efficacy of efavirenz (DMP‐266), MSC194 and PNU142721 towards the HIV‐1 RT K103N mutant

Lindberg

Sigurðsson

Löwgren

et al. 2002

European Journal of Biochemistry

136

135

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The K103N substitution is a frequently observed HIV-1 RT mutation in patients who do not respond to combinationtherapy. The drugs Efavirenz, MSC194 and PNU142721 belong to the recent generation of NNRTIs characterized by an improved resistance profile to the most common single point mutations within HIV-1 RT, including the K103N mutation. In the present study we present structural observations from Efavirenz in complex with wild-type protein and the K103N mutant and PNU142721 and MSC194 in complex with the K103N mutant. The structures unanimously indicate that the K103N substitution induces only minor positional adjustments of the three inhibitors and the residues lining the binding pocket. Thus, compared to the corresponding wild-type structures, these inhibitors bind to the mutant in a conservative mode rather than through major rearrangements. The structures implicate that the reduced inhibitory efficacy should be attributed to the changes in the chemical environment in the vicinity of the substituted N103 residue. This is supported by changes in hydrophobic and electrostatic interactions to the inhibitors between wild-type and K103N mutant complexes. These potent inhibitors accommodate to the K103N mutation by forming new interactions to the N103 side chain. Our results are consistent with the proposal by Hsiou et al. [Hsiou, Y., Ding, J., Das, K., Clark, A.D. Jr, Boyer, P.L., Lewi, P., Janssen, P.A., Kleim, J.P., Rosner, M., Hughes, S.H. & Arnold, E. (2001) J. Mol. Biol. 309, 437-445] that inhibitors with good activity against the K103N mutant would be expected to have favorable interactions with the mutant asparagines side chain, thereby compensating for resistance caused by stabilization of the mutant enzyme due to a hydrogen-bond network involving the N103 and Y188 side chains.Keywords: drug-resistance; HIV; NNRTI; reverse transcriptase.The use of highly active antiretroviral therapy (HAART) involving multidrug combinations has significantly reduced the death rates of HIV-1 infected individuals receiving such treatment [1]. Inhibitors of the HIV-1 reverse transcriptase (RT) constitute a cornerstone in this therapy and are commonly used in combination with inhibitors of the HIV-1 protease. The RT inhibitors belong to two classes, the nucleoside inhibitors and the non-nucleoside inhibitors (NNRTI). Whereas the NRTIs are nucleoside analogues with chain-terminating properties and affinity to active site residues, the NNRTIs include a wide range of series of chemical compounds characterized by noncompetitive binding to an allosteric site some 10 Å away from the active site. Structural comparison of RT in complex with template/primer and NNRTIs together with native RT complexes have shown that the NNRTIs inhibit the polymerase activity through long-range and short-range structural distortions in several of the RT subdomains. The distortions involve repositioning of residues in the nonnucleoside binding pocket (NNIBP) that impose steric impediments on the thumb subdomain flexibility forcing it to remain in the ...

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“…1) represents a new NNRTI agent (De Clercq, 2001, 2002Fujiwara et al, 1998Fujiwara et al, , 1999Ohkawa et al, 1998;Ren et al, 2000). Capravirine inhibits replication of HIV-1 strains that are resistant to nucleoside/nucleotide reverse transcriptase inhibitors and other NNRTIs, and is more potent than nevirapine and delavirdine of this class (Fujiwara et al, 1998).…”

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confidence: 99%

Metabolism and Excretion of Capravirine, a New Non-Nucleoside Reverse Transcriptase Inhibitor, Alone and in Combination With Ritonavir in Healthy Volunteers

Bu¹,

Pool²,

Wu³

et al. 2004

Drug Metab Dispos

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ABSTRACT:Metabolism and disposition of capravirine, a new non-nucleoside reverse transcriptase inhibitor, were studied in healthy male volunteers who were randomly divided into two groups (A and B) with five subjects in each group. Group A received a single oral dose of [ 14 C]capravirine (1400 mg) and group B received multiple oral doses of ritonavir (100 mg), followed by a single oral dose of [ 14 C]capravirine (1400 mg). Mean total recoveries of radioactivity for groups A and B were 86.3% and 79.0%, respectively, with a mean cumulative recovery in urine comparable with that in feces for both groups. Excretion of unchanged capravirine was negligible in urine and low in feces for both groups. The results suggest that capravirine was well absorbed, with metabolism as the principal mechanism of clearance. Capravirine underwent extensive metabolism to a variety of metabolites via oxygenations (mono-, di-, tri-, and tetra-) representing the predominant pathway, glucuronidation, and sulfation in humans. No useful plasma profiles of group A were obtained due to extremely low levels of plasma radioactivity. Analysis of group B plasma indicated that unchanged capravirine was the major radiochemical component, with three monooxygenated products and a glucuronide of capravirine as the major circulating metabolites. Nineteen metabolites were identified using liquid chromatography-multistage ion-trap mass spectrometry methodologies. In summary, coadministration of lowdose ritonavir (a potent CYP3A4 inhibitor) drastically decreased the levels of sequential oxygenated metabolites and markedly increased the levels of the parent drug and primary oxygenated metabolites overall in plasma, urine, and feces.

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Binding of the Second Generation Non-nucleoside Inhibitor S-1153 to HIV-1 Reverse Transcriptase Involves Extensive Main Chain Hydrogen Bonding

Cited by 130 publications

References 30 publications

Combining structure-based drug design and pharmacophores

Combining structure-based drug design and pharmacophores

Structural basis for the inhibitory efficacy of efavirenz (DMP‐266), MSC194 and PNU142721 towards the HIV‐1 RT K103N mutant

Metabolism and Excretion of Capravirine, a New Non-Nucleoside Reverse Transcriptase Inhibitor, Alone and in Combination With Ritonavir in Healthy Volunteers

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