Docking of non‐nucleoside inhibitors: Neotripterifordin and its derivatives to HIV‐1 reverse transcriptase

Zhou, Zhigang; Madrid, Marcela; Madura, Jeffry D.

doi:10.1002/prot.10233

Cited by 21 publications

(28 citation statements)

References 41 publications

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“…Hydrogen atoms and partial charges were added to the enzyme by MOE using the Kollman94 force field. MOE used the PEOE method to assign partial charges for the FAD cofactors and duroquinone (22)(23)(24). After all non-hydrogen atoms were fixed, the molecule was energy minimized by a combination minimization method comprised of steepest descent, conjugate gradient, and truncated Newton (25).…”

Section: Methodsmentioning

confidence: 99%

Kinetic and Docking Studies of the Interaction of Quinones with the Quinone Reductase Active Site

et al. 2003

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NAD(P)H/quinone acceptor oxidoreductase type 1 (QR1) protects cells from cytotoxic and neoplastic effects of quinones though two-electron reduction. Kinetic experiments, docking, and binding affinity calculations were performed on a series of structurally varied quinone substrates. A good correlation between calculated and measured binding affinities from kinetic determinations was obtained. The experimental and theoretical studies independently support a model in which quinones (with one to three fused aromatic rings) bind in the QR1 active site utilizing a π-stacking interaction with the isoalloxazine ring of the FAD cofactor. NAD(P)H:quinone acceptor oxidoreductase type 1 (QR1, 1 EC 1.6.99.2), a homodimeric flavoprotein of 273 residues (M ) 30815) per monomer, catalyzes an obligatory twoelectron reduction of quinones using either NADH or NADPH as electron donors (1, 2). QR1 affords protection against the cytotoxic and neoplastic effects of electrophilic quinones and partially reduced semiquinones that can undergo redox cycling to generate active oxygen species (3). QR1, found in many solid tumors at elevated levels, can be used to target the tumor cells through bioreductive activation of quinone-based chemotherapeutic agents (3).The crystal structures of quinone reductases from rat (PDB ID: 1QRD), mouse (1DXQ), and human (1DXO, 1D4A), reflecting a high degree of sequence identity, show very small differences in the positions of the 220 R-carbons in the catalytic domain and possess nearly identical active sites (1,4,5). The crystal structure for the rat enzyme (1QRD) contains duroquinone, FAD, and the NAD(P)H analogue cibracon blue, but the latter ligand sterically intrudes into the active site, affecting the position of at least one key residue, Tyr128 (1, 4). The human enzyme, whose crystal structure (1DXO) contains duroquinone and FAD but no cibracon blue, differs from the rat enzyme by one amino acid (Gln104 in human, Tyr104 in rat) in the active site, resulting in a slight change (0.7 Å) in the positioning of the flavin ring (1).The quinone reductase active site, produced by residues from each subunit of the dimeric protein, has the following features: (1) the duroquinone overlays the FAD isoalloxazine ring that is bound to one subunit, with the quinoid carbonyl oxygens oriented roughly parallel to the length of the flavin ring; (2) a loop from the second subunit, which forms a lid for the active site above the bound quinone, provides two tyrosine residues, Tyr126 and Tyr128, that hydrogen bond directly, or indirectly via a water molecule, to the quinone carbonyl groups; and (3) three aromatic residues provide hydrophobic contacts with the quinone, and one of these, Trp105, forms a wall bordering one side of the active site (1). A depiction of the human quinone reductase (1DXO) active site is shown in Figure 1.Mechanistically, a hydride ion from NAD(P)H is thought to be transferred to the flavin nitrogen, N 5 , with possible charge stabilization from a catalytic triad involving the FAD, Tyr155, ...

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Section: Methodsmentioning

confidence: 99%

Kinetic and Docking Studies of the Interaction of Quinones with the Quinone Reductase Active Site

et al. 2003

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“…Experimental anti-HIV activity (pIC50) complied from references [10][11][12][13]. From the result of the QSAR study, it appears that the presence of halogen atom at X position with Balaben index will increase the HIV-1 binding affinity of TIBO derivatives.…”

Section: Utility Of Topological Parametermentioning

confidence: 99%

“…Experimental anti-HIV activity (pIC50) complied from references [10,11]. For the dataset of 16 analogues with well-defined activity, the HIV-1 non nucleoside reverse transcriptase inhibitory potency appears to be influenced by structural components.…”

Section: Utility Of Non-conventional Topological Parametermentioning

confidence: 99%

TIBO Derivatives as an Anti HIV Agent- QSAR and its Utility

Ojha

2018

JAPLR

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“…In docking studies, different search algorithms such as simulated annealing and genetic algorithm in combination with scoring function such as molecular mechanic calculations are used to study the binding of the candidate ligands to an enzyme with known structure. Docking studies involving NNI's and HIV-1 RT have been performed previously [28][29][30][31][32][33][34][35][36]. The results have shown that most inhibitors can docked into their crystal structure position.…”

Section: Introductionmentioning

confidence: 97%

“…Thus, they are simple, non-expensive and expedite to design molecules with desirable biological activity [27]. Quantitative structureactivity relationship (QSAR) [16][17][18][19][20][21][22][23] and docking procedure [24][25][26][27][28][29] are two mostly used computational methods in drug design. In QSAR methodologies, a mathematical relationship, relating the biological activity to some molecular descriptors is obtained.…”

Section: Introductionmentioning

confidence: 99%

Docking studies on the effect of β-ring expansion in binding of TIBO derivatives to HIV-1 reverse transcriptase

Hemmateenejad

Tabaei

Namvaran

2007

JICS

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Designing of new inhibitors to human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) is one of the important research area in AIDS therapies. Non-nucleoside inhibitors of reverse transcriptase (NNIRT) are attractive drug candidates for their unique binding site to the reverse HIV-1 RT and less adverse side effects. The effect of expansion of diazepine ring from seven to eight in some tetrahydroimidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-thione (TIBO) derivatives as NNIRT has been investigated by docking procedure. Sixteen conventional TIBO derivatives with known HIV-1 RT inhibitor activity were selected and their -ring was expanded to eight. The three-dimensional (3D) geometry of the molecules was optimized by AM1 semiempirical method and then interacted with the HIV-1 RT enzyme using Autodock program. Twelve out of sixteen of the new molecules were docked into the enzyme. The resulted free energies of docking indicated that the newly proposed molecules bond to the enzyme with comparable tendency in relative to their corresponding conventional homologous. It was found that three new compounds bind to the receptor stronger than that of their corresponding 7-membered ring derivatives and can be considered as new candidate for synthesis.

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Docking of non‐nucleoside inhibitors: Neotripterifordin and its derivatives to HIV‐1 reverse transcriptase

Cited by 21 publications

References 41 publications

Kinetic and Docking Studies of the Interaction of Quinones with the Quinone Reductase Active Site

Kinetic and Docking Studies of the Interaction of Quinones with the Quinone Reductase Active Site

TIBO Derivatives as an Anti HIV Agent- QSAR and its Utility

Docking studies on the effect of β-ring expansion in binding of TIBO derivatives to HIV-1 reverse transcriptase

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