HIV-Reverse Transcriptase Inhibition:  Inclusion of Ligand-Induced Fit by Cross-Docking Studies

Ragno, Rino; Frasca, Simona; Manetti, Fabrizio; Brizzi, Antonella; Massa, S.

doi:10.1021/jm0493921

Cited by 67 publications

(60 citation statements)

References 58 publications

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“…This information potentially leads to more flexible RT inhibitors with a broader range of activity against NNRTI-resistant mutants. [12] This hypothesis was confirmed by the synthesis and characterization of 2,6-difluoro-substituted N,N-DABO derivatives, which proved to be superior to the corresponding NH-DABOs both in…”

Section: Introductionmentioning

confidence: 78%

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Substrate‐Induced Stable Enzyme–Inhibitor Complex Formation Allows Tight Binding of Novel 2‐Aminopyrimidin‐4(3H)‐ones to Drug‐Resistant HIV‐1 Reverse Transcriptase Mutants

Samuele¹,

Facchini²,

Rotili³

et al. 2008

ChemMedChem

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We recently reported the synthesis and biological evaluation of a novel series of 5-alkyl-2-(N,N-disubstituted)amino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones (F(2)-N,N-DABOs). These compounds are highly active against both wild-type HIV-1 and the K103N, Y181C, and Y188L mutant strains. Herein we present novel 6-(2-chloro-6-fluorophenylalkyl)-N,N-DABO (2-Cl-6-F-N,N-DABO) derivatives and investigate the molecular basis for their high-affinity binding to HIV-1 reverse transcriptase (RT). Our results show that the new compounds display higher association rates than the difluoro derivatives toward wild-type HIV-1 RT or drug-resistant RT mutant forms. We also show that they preferentially associate to either the free enzyme or the enzyme-nucleic acid binary complex, and that this binding is stabilized upon formation of the ternary complex between HIV-1 RT and both the nucleic acid and nucleotide substrates. Interestingly, one compound showed dissociation rates from the ternary complex with RT mutants K103N and Y181I 10-20-fold slower than from the corresponding complex with wild-type RT.

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Section: Introductionmentioning

confidence: 78%

“…The homopolymer poly(rA) and the oligomer oligo(dT) [12][13][14][15][16][17][18] (Pharmacia & Upjohn Inc. (Pfizer, Peapack, NJ, USA)) were mixed at weight ratios in nucleotides of 10:1 with 25 mm Tris HCl (pH 8.0) containing 22 mm KCl, heated at 70 8C for 5 min and then slowly cooled to room temperature.…”

Section: Nucleic Acid Substratesmentioning

confidence: 99%

Substrate‐Induced Stable Enzyme–Inhibitor Complex Formation Allows Tight Binding of Novel 2‐Aminopyrimidin‐4(3H)‐ones to Drug‐Resistant HIV‐1 Reverse Transcriptase Mutants

Samuele¹,

Facchini²,

Rotili³

et al. 2008

ChemMedChem

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“…Also crystal structure analysis of HIV-RT enzyme showed that most of NNRTIs bound to the enzyme in a ''butterfly like'' mode (Schiifer et al, 1993;Ragno et al, 2005). One of the wings of this butterfly is made of p electron rich moiety (phenyl or allyl substituents) that interact through p-p interaction with a hydrophobic pockets formed mainly by the side chains of aromatic amino acids (Tyr 181, Tyr188, Phe227, Trp229, Tyr318).…”

Section: Design Of New Chemical Entitiesmentioning

confidence: 99%

Design, docking study and ADME prediction of Isatin derivatives as anti-HIV agents

Pawar¹,

Lokwani²,

Bhandari³

et al. 2010

Med Chem Res

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Non-nucleoside reverse transcriptase inhibitors (NNRTI) has a definitive role and most commonly used in treatment of HIV infection. NNRTI act by binding to specific binding site (non-nucleoside binding pocket-NNBP) in reverse transcriptase (RT) enzyme. With the objective of developing efficient NNRTI, we have designed various Isatin analogs for effective treatment of AIDS and were subjected to molecular docking studies on five different crystal structures of RT complexed with five different ligands Nevirapine, Delaviridine, Efavirenz, Etravirine, and Rilpivirine. Combined dock-score of compound N21, N11, N23 was found to be comparable with standards indicated that Isatin analogs have good binding affinity for NNBP. Docking results suggested that these types of compounds could be binding in the NNRTI binding site in a similar mode to a known non-nucleoside inhibitors. ADME properties of Isatin analogs were also analyzed using Qikprop 2.5 tool of Schrodinger software.

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“…Thus, different chemical and structural features of the inhibitors and their side-chain flexibility make the bound nonnucleoside binding pockets to undergo different conformation changes. In addition, mutations of a few amino acids also cause a variation of the nonnucleoside binding pocket properties, which can decrease the affinity of most of the inhibitors [10,11].…”

Section: Introductionmentioning

confidence: 99%

A Battle Against Aids: New Pyrazole Key to an Older Lock-Reverse Transcriptase

Jacob

Ganguly

2016

Int J Pharm Pharm Sci

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Objective: The reason for the failure of most of the anti-HIV drugs are their poor pharmacokinetics, the poor risk to benefit ratio and the drug resistance. With the objective of developing newer pyrazole scaffolds for effective treatment of HIV, binding mode analysis of designing ligands with the HIV-1RT protein and prediction of key ADME and toxicity parameters of the compounds was in an area of interest. Methods:In this study, molecular docking studies and ADME-T studies were carried out in designing of some novel pyrazole analogs. The protein (PDB ID: 1RT2) was prepared using the Protein Preparation Wizard (Schrodinger Glide 5.0). ADME parameters calculated by QikProp 3.0v and toxicity of designed analogs checked by using two different online software's namely Lazar and protox.Results: Most of the designed pyrazole analogs have good oral absorption as well as good binding affinity towards HIV-1 reverse transcriptase. Conclusion:Finally total 5 analogs (SGS-2, 3, 12, 13 and 14) from the 14 designed leads were found to be best on the basis of molecular docking and ADME-T studies.

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HIV-Reverse Transcriptase Inhibition: Inclusion of Ligand-Induced Fit by Cross-Docking Studies

Cited by 67 publications

References 58 publications

Substrate‐Induced Stable Enzyme–Inhibitor Complex Formation Allows Tight Binding of Novel 2‐Aminopyrimidin‐4(3H)‐ones to Drug‐Resistant HIV‐1 Reverse Transcriptase Mutants

Substrate‐Induced Stable Enzyme–Inhibitor Complex Formation Allows Tight Binding of Novel 2‐Aminopyrimidin‐4(3H)‐ones to Drug‐Resistant HIV‐1 Reverse Transcriptase Mutants

Design, docking study and ADME prediction of Isatin derivatives as anti-HIV agents

A Battle Against Aids: New Pyrazole Key to an Older Lock-Reverse Transcriptase

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