In silico evaluation of atazanavir as a potential HIV main protease inhibitor and its comparison with new designed analogs

Yoosefian, Mehdi; Moghani, Maryam Zeraati; Juan, Alfredo

doi:10.1016/j.compbiomed.2022.105523

Cited by 6 publications

(5 citation statements)

References 41 publications

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“…Another approach for safer PIs is screening a large database of active molecules or designing multiple analogs of current PI drugs through structure-based molecular docking and simulation analysis [187]. An analog of ATV has been screened out with a greater inhibitory capacity on HIV-1 aspartyl protease and less off-target effect/hepatotoxicity than the original ATV drug [188].…”

Section: Designing Safer Pismentioning

confidence: 99%

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

Cheng

2023

IJMS

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Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4α, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.

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Section: Designing Safer Pismentioning

confidence: 99%

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

Cheng

2023

IJMS

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“…Several modern techniques have been used to examine drug–protein interactions, including surface plasmon resonance [ 6 ], graph neural networks [ 7 ], multispectroscopic analysis [ 8 ], molecular docking and molecular dynamics simulations [ 9 , 10 ], and chromatographic methods [ 11 ]. Among these methodologies, quantitative affinity chromatography is extremely powerful.…”

Section: Introductionmentioning

confidence: 99%

Immobilization of M3 Muscarinic Receptor to Rapidly Analyze Drug—Protein Interactions and Bioactive Components in a Natural Plant

Fan

Huang

Zhang

et al. 2023

IJMS

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Despite its increasing application in pursing potential ligands, the capacity of receptor affinity chromatography is greatly challenged as most current research studies lack a comprehensive characterization of the ligand–receptor interaction, particularly when simultaneously determining their binding thermodynamics and kinetics. This work developed an immobilized M3 muscarinic receptor (M3R) affinity column by fixing M3R on amino polystyrene microspheres via the interaction of a 6-chlorohexanoic acid linker with haloalkane dehalogenase. The efficiency of the immobilized M3R was tested by characterizing the binding thermodynamics and kinetics of three known drugs to immobilized M3R using a frontal analysis and the peak profiling method, as well as by analyzing the bioactive compounds in Daturae Flos (DF) extract. The data showed that the immobilized M3R demonstrated good specificity, stability, and competence for analyzing drug–protein interactions. The association constants of (−)-scopolamine hydrochloride, atropine sulfate, and pilocarpine to M3R were determined to be (2.39 ± 0.03) × 104, (3.71 ± 0.03) × 104, and (2.73 ± 0.04) × 104 M−1, respectively, with dissociation rate constants of 27.47 ± 0.65, 14.28 ± 0.17, and 10.70 ± 0.35 min−1, respectively. Hyoscyamine and scopolamine were verified as the bioactive compounds that bind to M3R in the DF extract. Our results suggest that the immobilized M3R method was capable of determining drug–protein binding parameters and probing specific ligands in a natural plant, thus enhancing the effectiveness of receptor affinity chromatography in diverse stages of drug discovery.

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“…HIV‐1 reverse transcriptase (RT) plays a crucial role in the replication of HIV‐1. HIV‐1 RNA is inverted into cDNA under the action of RT to form RNA‐DNA intermediates, and the RNA‐DNA intermediates then replicated into intact duplex DNA with the remaining cDNA as a template utilizing the hydrolysis of RT [3,4] . Hence, HIV‐1 replication can be effectively blocked by inhibiting HIV RT, and HIV‐1 RT has been identified as one of the top targets for research into the therapy of HIV‐1.…”

Section: Introductionmentioning

confidence: 99%

“…HIV-1 RNA is inverted into cDNA under the action of RT to form RNA-DNA intermediates, and the RNA-DNA intermediates then replicated into intact duplex DNA with the remaining cDNA as a template utilizing the hydrolysis of RT. [3,4] Hence, HIV-1 replication can be effectively blocked by inhibiting HIV RT, and HIV-1 RT has been identified as one of the top targets for research into the therapy of HIV-1. HIV-1 RT can be suppressed by two types of inhibitors belonging either to the nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) or to the non-NRTIs (NNRTIs).…”

Section: Introductionmentioning

confidence: 99%

Drug Design, Molecular Docking and Molecular Dynamics Simulations of Indole Class HIV‐1 NNRTIs Explored with QSAR and Topomer Search

et al. 2023

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HIV reverse transcriptase (RT) as one of the key targets for the treatment of HIV, and in recent years a series of indole class non‐nucleoside reverse transcriptase inhibitors (NNRTIs) with potent anti‐HIV‐1 properties have been reported. In this paper, Topomer CoMFA model with reliable validation results (q2=0.809, R2=0.983, R2pred=0.870) for exploring the quantitative structure‐activity relationship (QSAR) of the inhibitors. And the relationship between molecular structures and activities were further analysed using the contour plots. The Topomer search technique was employed to search and then designed novel compounds with stronger inhibitory effects. Molecular docking showed that the residue LYS101, GLU138 and ILE180 played a key role, meanwhile, the stability of the docking results was verified by molecular dynamics simulations (MD). Finally, the calculated results of the binding free energy calculations agree with the predictions of the model, further validating the reliability of the proposed model.

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In silico evaluation of atazanavir as a potential HIV main protease inhibitor and its comparison with new designed analogs

Cited by 6 publications

References 41 publications

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

Immobilization of M3 Muscarinic Receptor to Rapidly Analyze Drug—Protein Interactions and Bioactive Components in a Natural Plant

Drug Design, Molecular Docking and Molecular Dynamics Simulations of Indole Class HIV‐1 NNRTIs Explored with QSAR and Topomer Search

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