ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans.

Kempf, Dale J.; Marsh, Kennan C.; Denissen, Jon F.; McDonald, Edith; Vasavanonda, Sudthida; Flentge, Charles A.; Green, B E; Fino, Lynnmarie; Park, C H; Kong, X.P.

doi:10.1073/pnas.92.7.2484

Cited by 519 publications

(338 citation statements)

References 20 publications

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“…The red-shifted absorption maximum of the ferrous ritonavir-bound CYP3A4 resembles that observed for the metyrapone-bound cytochrome P450cam and may be attributed to the σ-donor nitrogen ligation to the heme iron (16). Given that the thiazole and isopropyl-thiazole groups of ritonavir are strictly required for potent inhibition (9), and ketoconazole, another type II inhibitor of CYP3A4, binds to the heme iron via the imidazole nitrogen (17), it can be concluded based on the spectral data that the thiazole nitrogen of ritonavir is the likely iron ligand in both ferric and ferrous CYP3A4.…”

Section: Resultsmentioning

confidence: 99%

“…This kinetic behavior, as well as increased inhibitory potency of ritonavir after preincubation with microsomes suggest that the drug is a mechanism-based inhibitor which converts into a reactive intermediate upon oxidation and selectively inactivates CYP3A4 by irreversibly attaching to the heme and/or active site amino acid residues (7,8). The reactive intermediate(s) was proposed to involve the isopropyl-thiazole end-group (7), strictly required for potent CYP3A4 inhibition (9). Further, a noncovalent inhibitory complex, also known as a metabolic intermediate complex (MIC) (10), was reported to form during incubation of ritonavir with insect microsomes containing recombinantly expressed human CYP3A4 and cytochrome b 5 (11).…”

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confidence: 99%

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Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir

Sevrioukova

Poulos

2010

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

244

281

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Ritonavir is a HIV protease inhibitor routinely prescribed to HIV patients that also potently inactivates cytochrome P4503A4 (CYP3A4), the major human drug-metabolizing enzyme. By inhibiting CYP3A4, ritonavir increases plasma concentrations of other anti-HIV drugs oxidized by CYP3A4 thereby improving clinical efficacy. Despite the importance and wide use of ritonavir in anti-HIV therapy, the precise mechanism of CYP3A4 inhibition remains unclear. The available data are inconsistent and suggest that ritonavir acts as a mechanism-based, competitive or mixed competitivenoncompetitive CYP3A4 inactivator. To resolve this controversy and gain functional and structural insights into the mechanism of CYP3A4 inhibition, we investigated the ritonavir binding reaction by kinetic and equilibrium analysis, elucidated how the drug affects redox properties of the hemoprotein, and determined the 2.0 Å X-ray structure of the CYP3A4-ritonavir complex. Our results show that ritonavir is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase.crystal structure | cytochrome P450 | inhibitor

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir

Sevrioukova

Poulos

2010

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

244

281

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“…Such a binding-site arrangement at the protein interface is also seen in other types of ATPases, such as the rotary F-ATPases, which utilize heterodimeric interfaces instead to capture ATP/ADPs. The last example is HIV-1 protease, which is a prime drug target for treating AIDS caused by the virus (31). Fig.…”

Section: Resultsmentioning

confidence: 99%

The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation

Gao

Skolnick

2012

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

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Protein-protein and protein-ligand interactions are ubiquitous in a biological cell. Here, we report a comprehensive study of the distribution of protein-ligand interaction sites, namely ligand-binding pockets, around protein-protein interfaces where protein-protein interactions occur. We inspected a representative set of 1,611 representative protein-protein complexes and identified pockets with a potential for binding small molecule ligands. The majority of these pockets are within a 6 Å distance from protein interfaces. Accordingly, in about half of ligand-bound protein-protein complexes, amino acids from both sides of a protein interface are involved in direct contacts with at least one ligand. Statistically, ligands are closer to a protein-protein interface than a random surface patch of the same solvent accessible surface area. Similar results are obtained in an analysis of the ligand distribution around domain-domain interfaces of 1,416 nonredundant, two-domain protein structures. Furthermore, comparable sized pockets as observed in experimental structures are present in artificially generated protein complexes, suggesting that the prominent appearance of pockets around protein interfaces is mainly a structural consequence of protein packing and thus, is an intrinsic geometric feature of protein structure. Nature may take advantage of such a structural feature by selecting and further optimizing for biological function. We propose that packing nearby protein-protein or domain-domain interfaces is a major route to the formation of ligand-binding pockets.packing | promiscuous interaction | protein structural evolution A t one point or another, virtually all biological processes are dependent on protein-protein and/or protein-ligand interactions (1). Since these interactions are ubiquitous for biological activity and are important to drug design, intense research efforts have been dedicated to elucidating their structural basis. This has resulted in the deposition of thousands of protein-protein and protein-ligand complexes in the PDB (2). From a structural prospective, protein surface regions directly contacting other proteins are known as protein-protein interfaces, whereas bindingsites for small molecule ligands are referred to as ligand-binding pockets.Using insights gleaned from high resolution structures, numerous studies have characterized protein-protein interfaces (3-6) and ligand-binding pockets (7,8). Protein interfaces are usually large, with a buried solvent accessible area of over 1;000 Å 2 (3). With the exception of intertwined interface structures, most protein interfaces have planar shapes (4, 9, 10). Although there are in principle millions of ways of forming protein-protein interfaces, a recent study has revealed that the structural space of protein interfaces is surprisingly small, primarily attributed to limited ways of protein secondary structural packing and the flatness of interfaces (10). This affords the possibility of convergent evolution for common biological functions. In contrast...

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“…HIV protease inhibitors (PIs) have revolutionized the treatment of HIV infection (Roberts et al, 1990;Vacca et al, 1994;Danner et al, 1995;Kempf et al, 1995;Patick et al, 1996). Due to limited oral bioavailability and poor pharmacokinetics of many of the currently available PIs, additional efforts have been made to design more potent PIs with improved pharmacokinetic properties.…”

Section: Introductionmentioning

confidence: 99%

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Agarwal

Pal

Mitra

2007

International Journal of Pharmaceutics

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Polarized epithelial non-human (canine) cell lines stably transfected with human or murine complementary DNA (cDNA) encoding for various efflux transporters (P-gp/MDR1, MRP1, MRP2, and Bcrp1) were used to study transepithelial transport of Lopinavir (LVR) and compare results with the MDCKII-Wild type cells. These transmembrane proteins cause multidrug resistance by decreasing the total intracellular accumulation of drugs. Lopinavir efflux was directional and was completely inhibited by MK-571, a selective MRP family inhibitor in the MDCKII-MRP2 cell line. Similarly, LVR efflux was also inhibited by P-gp inhibitors P-gp 4008 and GF120918 in the MDCKII-MDR1 cell line. The efflux ratios (Efflux rate/ Influx rate) of LVR in the absence of any efflux inhibitors in the MDCK-Wild type, MDCKII-MDR1, MDCKII-MRP1 and MDCKII-MRP2 cell monolayers were 1.32, 4.91, 1.26 and 2.89 respectively. The MDCKII-MDR1 and MDCKII-MRP2 cells have significantly increased LVR efflux ratio relative to the parental cells due to the apically directed transport by MDR1 and MRP2 respectively. The efflux ratios in MRP2 and MDR1 transfected cell lines were close to unity in the presence of MK-571 and P-gp 4008 respectively; indicating that LVR efflux by MRP2 and P-gp was completely inhibited by their selective inhibitors. MDCKII-MRP1 cells did not exhibit a significant reduction in the LVR efflux relative to the parental cells, indicating that LVR is not a good substrate for MRP1. Transport studies across MDCKII-Bcrp1 cells indicated that LVR is not transported by Bcrp1 and is not a substrate for this efflux protein. In conclusion, this study presents direct evidence that LVR is effluxed by both P-gp and MRP2 which may contribute to its poor oral bioavailability and limited penetration into the CNS. KeywordsMDCKII-MDR1; MDCKII-MRP2; MDCKII-MRP1; MDCKII-Bcrp1; MDCKII-WT; Pglycoprotein (P-gp); multidrug resistance protein (MRP); breast cancer resistance protein (BCRP); Lopinavir (LVR); uptake; transport; permeability; efflux ratio (ER)

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ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans.

Cited by 519 publications

References 20 publications

Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir

Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir

The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

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