Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

Liu, Genyan; Wang, Wenjie; Wan, Youlan; Ju, Xin; Gu, Shuang‐Xi

doi:10.3390/ijms19051436

Cited by 27 publications

(18 citation statements)

References 28 publications

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“…Some docking studies have been performed on already available drug compounds to rank their potential for development as antiviral agents [20,21]. Studies using molecular docking have been utilized to analyze binding interactions of antiviral compounds targeting; the HIV protease [22,23], topoisomerase II DNA gyrase enzymes [24,25], and anti-cancer compounds which target histone deacetylases [26][27][28] and a range of other diseases can assist in the optimization of molecular interactions for drug design. Studies performed to explore the broad substrate binding preferences that SARS-CoV-2 M pro has would therefore significantly assist in the optimization of any lead drug compounds that are being pursued.…”

Section: Introductionmentioning

confidence: 99%

Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site

Stoddard

Oelkers

et al. 2020

Viruses

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Coronaviruses are viral infections that have a significant ability to impact human health. Coronaviruses have produced two pandemics and one epidemic in the last two decades. The current pandemic has created a worldwide catastrophe threatening the lives of over 15 million as of July 2020. Current research efforts have been focused on producing a vaccine or repurposing current drug compounds to develop a therapeutic. There is, however, a need to study the active site preferences of relevant targets, such as the SARS-CoV-2 main protease (SARS-CoV-2 Mpro), to determine ways to optimize these drug compounds. The ensemble docking and characterization work described in this article demonstrates the multifaceted features of the SARS-CoV-2 Mpro active site, molecular guidelines to improving binding affinity, and ultimately the optimization of drug candidates. A total of 220 compounds were docked into both the 5R7Z and 6LU7 SARS-CoV-2 Mpro crystal structures. Several key preferences for strong binding to the four subsites (S1, S1′, S2, and S4) were identified, such as accessing hydrogen binding hotspots, hydrophobic patches, and utilization of primarily aliphatic instead of aromatic substituents. After optimization efforts using the design guidelines developed from the molecular docking studies, the average docking score of the parent compounds was improved by 6.59 −log10(Kd) in binding affinity which represents an increase of greater than six orders of magnitude. Using the optimization guidelines, the SARS-CoV-2 Mpro inhibitor cinanserin was optimized resulting in an increase in binding affinity of 4.59 −log10(Kd) and increased protease inhibitor bioactivity. The results of molecular dynamic (MD) simulation of cinanserin-optimized compounds CM02, CM06, and CM07 revealed that CM02 and CM06 fit well into the active site of SARS-CoV-2 Mpro [Protein Data Bank (PDB) accession number 6LU7] and formed strong and stable interactions with the key residues, Ser-144, His-163, and Glu-166. The enhanced binding affinity produced demonstrates the utility of the design guidelines described. The work described herein will assist scientists in developing potent COVID-19 antivirals.

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Section: Introductionmentioning

confidence: 99%

Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site

Stoddard

Oelkers

et al. 2020

Viruses

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“…Next, all of the candidate compounds were docked into the binding pocket, and 20 possible docked conformations were obtained with different scores. 36,37 Molecular modeling figure was drawn using PyMOL software (http://www.pymol.org). 38 mTOR Enzyme Assay LANCE ® ultra time-resolved fluorescence resonance energy transfer (TR-FRET) assay (Invitrogen, Carlsbad, CA, USA) was used to determine the mTOR kinase activities of all the compounds following the manufacturer's instructions, with compound GSK2126458 (Selleck, China) as positive control.…”

Section: Molecular Dockingmentioning

confidence: 99%

<p>Novel mTOR Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeting Agents</p>

Feng¹,

Li²,

Feng³

et al. 2020

OTT

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Background: Although molecular-targeted agents are still the first choice for advanced hepatocellular carcinoma (HCC) treatment, the therapeutic efficacy of these agents is not satisfactory. Recently, the mammalian target of rapamycin (mTOR) is considered to be a promising molecular target that can enhance the sensitivity of HCC cells to antitumor therapy. However, the reported mTOR inhibitors have some shortcomings, and novel mTOR inhibitors need to be developed to enhance the antitumor effect of molecularly targeted agents on advanced HCC. Methods: In this study, five small-molecular compounds that could serve as potential mTOR-specific inhibitors were identified by virtual screening. The activity of tert-butyl (4-(9-(2-(1,3-dioxolan-2-yl)ethyl)-6-morpholino-9H-purin-2-yl)phenyl)carbamate (compound 4) was measured by enzyme test and Western blot, and its antitumor effect on HCC was examined in nude mice subcutaneous tumor model. Results: The results showed that 4 is the most effective one in inhibiting the activation of mTOR kinase (mTOR IC 50 = 17.52±3.67 nmol/L) among the five lead compounds. Further research in this study indicated that treatment with 4 enhanced the sensitivity of HCC cells to the molecular-targeted agents, such as sorafenib, regorafenib, lenvatinib, anlotinib, and apatinib. In addition, this research indicated that mTOR was correlated with the poor prognosis in patients with advanced HCC who received sorafenib. Conclusion: Our study identified a new type of small-molecular inhibitors of mTOR and confirmed their ability to enhance the antitumor effect of molecular-targeted agents on advanced HCC.

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“…In order to find compounds with new scaffolds, pharmacophore modeling and molecular docking were used to screen our library of 2063 small compounds in this study. 43,44 The compounds were obtained from several research groups and most of them have not been previously reported; among them, 1276 compounds were serine/threonine kinase inhibitors with structural diversity.…”

Section: Identification Of Lead Compoundmentioning

confidence: 99%

<p>Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma</p>

Feng¹,

Gu²,

Yong-Shou³

et al. 2020

DDDT

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Background: Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC. Methods: A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K. The radiosensitizing effect of the optimized compound (2a) was confirmed by colony formation assays and DNA double-strand break assays in vitro. The discovery and preclinical characteristics of this compound are described. Results: The key amino acid residues in mTOR were identified, and a precise virtual screening model was constructed. Compound 2a, with a 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine scaffold, exhibited promising potency against mTOR (mTOR IC 50 =7.1 nmol/L (nM)) with 126-fold selectivity over PI3Kα. Moreover, 2a significantly enhanced the sensitivity of HCC to radiotherapy in vitro in a dose-dependent manner. Conclusion: A new class of selective mTOR inhibitors was developed and their radiosensitization effects were confirmed. This study also provides a basis for developing mTORspecific inhibitors for use as radiosensitizers for HCC radiotherapy.

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Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors

Cited by 27 publications

References 28 publications

Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site

Optimization Rules for SARS-CoV-2 Mpro Antivirals: Ensemble Docking and Exploration of the Coronavirus Protease Active Site

<p>Novel mTOR Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeting Agents</p>

<p>Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma</p>

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