3D-QSAR and molecular docking studies on designing inhibitors of the hepatitis C virus NS5B polymerase

Li, Wenlian; Si, Hongzong; Li, Yang; Ge, Cuizhu; Song, Fuhang; Ma, Xiuting; Duan, Yun‐Bo; Zhai, Hongbin

doi:10.1016/j.molstruc.2016.03.073

Cited by 25 publications

(7 citation statements)

References 59 publications

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“…According to the total docking scores, the first twenty conformations of every ligand were saved. The best conformations of the ligands were analyzed for their binding interactions [ 40 ]. In the molecular docking process, the receptor protein was considered to be rigid, and the ligand compounds were regarded as being flexible [ 36 ].…”

Section: Methodsmentioning

confidence: 99%

Relationship between the binding free energy and PCBs’ migration, persistence, toxicity and bioaccumulation using a combination of the molecular docking method and 3D-QSAR

Zhao

Wang

Liu

2018

Chemistry Central Journal

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The molecular docking method was used to calculate the binding free energies between biphenyl dioxygenase and 209 polychlorinated biphenyl (PCB) congeners. The relationships between the calculated binding free energies and migration (octanol–air partition coefficients, KOA), persistence (half-life, t1/2), toxicity (half maximal inhibitory concentration, IC50), and bioaccumulation (bioconcentration factor, BCF) values for the PCBs were used to gain insight into the degradation of PCBs in the presence of biphenyl dioxygenase. The relationships between the calculated binding free energies and the molecular weights, KOA, BCF, and t1/2 values for the PCBs were statistically significant (P < 0.01), whereas the relationship between the calculated binding free energies and the IC50 for the PCBs was not statistically significant (P > 0.05). The electrostatic field, derived from three-dimensional quantitative structure–activity relationship studies, was a primary factor governing the binding free energy, which agreed with literature findings for KOA, t1/2, and BCF. Comparative molecular field analysis and comparative molecular similarity indices analysis contour maps showed that the binding free energies, KOA, t1/2, and BCF values for the PCBs decreased simultaneously when substituents with electropositive groups at the 3-position or electronegative groups at the 3′-position were introduced. This indicated the binding free energy was correlated with the persistent organic pollutant characteristics of PCBs. Furthermore, low binding free energies improved the degradation of the PCBs and simultaneously decreased the KOA, t1/2, and BCF values, thereby reducing the persistent organic pollutant characteristics of PCBs in the environment. These results are expected to be beneficial in providing a theoretical foundation for further elucidation of the degradation and molecular modification of PCBs.Electronic supplementary materialThe online version of this article (10.1186/s13065-018-0389-2) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Relationship between the binding free energy and PCBs’ migration, persistence, toxicity and bioaccumulation using a combination of the molecular docking method and 3D-QSAR

Zhao

Wang

Liu

2018

Chemistry Central Journal

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“…Due to its best reported biological activity, molecule 35 was selected as reference for molecular alignment. Each set was aligned using Sybyl "Align Database" function following maximum common substructure method [17].…”

Section: Molecule Alignmentmentioning

confidence: 99%

In-silico design of novel 4-aminoquinolinyl analogs as potential anti-malaria agents using quantitative structure– activity relationships and ADMET approach

Wu¹,

Wang²,

Li³

et al. 2020

Trop. J. Pharm Res

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Purpose: To design and screen for potential anti-malaria agents based on a series of 4-aminoquinolinyl analogues.Methods: Molecular fingerprint analysis was used for molecular partitioning of training and test sets. Acquired training sets were used for CoMFA and CoMSIA model construction after good alignment was achieved. Partial least squares analysis combined with external validation were used for model evaluation. Deep analysis of acquired contour maps was performed to summarize the substituent property requirements for further rational molecular design. Using the chosen models, activity prediction and subsequent ADMET investigation were performed to discover novel designed compounds with the desired properties.Results: Three different set partitions for model establishment were obtained using fingerprint-based selection. Partition 02 offered an optimal CoMFA model (r2 = 0.964, q2 = 0.605 and r2pred = 0.6362) and the best CoMSIA model (r2 = 0.955, q2 = 0.585 and r2 pred = 0.6403). Based on contour map analysis, a series of compounds were designed for activity prediction. Two of the compounds (wmx09, wmx25) were chosen for their ideal predicted biological activities. Subsequent ADMET investigation indicated that these compoundss have acceptable drug-like characteristics.Conclusion: The screening reveals that compounds wmx09 and wmx25 have strong potential as antimalaria agents. Keywords: Malaria, 4-Aminoquinolinyl, Molecular fingerprint, QSAR, ADMET

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“…Anti-HCV vaccination is currently unavailable; nonetheless, in the 1990s, interferon-alpha was used to treat HCV, and in the next decade, pegylated interferon-alpha in a mixture with ribavirin was used to treat HCV. Interferon-alpha inhibitors, DNA and RNA polymerase inhibitors, NS3/4A RNA protease inhibitors, NS5 RNA serine protease inhibitors, and NS5B RNA polymerase inhibitors have all been licensed for use in clinical trials since 2011 [1,4].…”

Section: Introductionmentioning

confidence: 99%

“…With advances in computational algorithms and simulation software, computer drug design has become widely used for drug discovery and development because of the advantages of being less time-consuming, cost-effective, and high effectiveness in silico screening and prediction of candidate medications [7]. Throughout the previous few decades, QSAR procedures have been developed and widely employed in a diversity of sectors, including chemical/biological, chemistry, and associated fields [4]. In this study, a QSAR model was proposed based on the structure of drugs having significant NS5B polymerase inhibitor bioactivity, and the model was externally validated to evaluate its genuine predictive capabilities.…”

Section: Introductionmentioning

confidence: 99%

Computational insight to design new potential hepatitis C virus NS5B polymerase inhibitors with drug-likeness and pharmacokinetic ADMET parameters predictions

et al. 2021

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Background Hepatitis C virus (HCV) is considered a worldwide health problem since it affects over 3% of the population and causes 300,000 fatalities per year. Chronic infection causes high morbidity and mortality in patients, leading to liver cirrhosis, hepatocellular carcinoma, fibrosis, liver cancer, and other HCV-related illnesses. Finding novel and better HCV treatments is a top international health goal right now. As a result, the pressing need for new HCV antiviral drugs has fueled research into the structural requirements of NS5B polymerase inhibitors at a molecular basis. Results In this study, an in silico technique was applied to study 79 compounds with HCV inhibitory bioactivity, with the best statistical results ($$R^{2}$$ R 2 = 0.7051, $$Q^{2}$$ Q 2 = 0.6455, $$R_{{{\text{pred}}}}^{2}$$ R pred 2 = 0.6992, $$^{{\text{c}}} R_{{\text{r}}}^{2}$$ c R r 2 = 0.6570, SEE = 0.2694). Conclusions This QSAR investigation allowed the research team to evaluate the influence of straightforward descriptors, shedding insight into the critical elements that guide the design of innovative effective molecules. Most of the innovative effective molecules exhibited better binding affinity (− 195.6 kcal/mol) than dasabuvir the reference drug (− 171.0 kcal/mol) with the target receptor (hepatitis C virus NS5B RNA polymerase). ADMET prediction disclosed enhanced pharmacokinetic properties with lower MRTD (maximum tolerated dose) of some new derivatives.

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3D-QSAR and molecular docking studies on designing inhibitors of the hepatitis C virus NS5B polymerase

Cited by 25 publications

References 59 publications

Relationship between the binding free energy and PCBs’ migration, persistence, toxicity and bioaccumulation using a combination of the molecular docking method and 3D-QSAR

Relationship between the binding free energy and PCBs’ migration, persistence, toxicity and bioaccumulation using a combination of the molecular docking method and 3D-QSAR

In-silico design of novel 4-aminoquinolinyl analogs as potential anti-malaria agents using quantitative structure– activity relationships and ADMET approach

Computational insight to design new potential hepatitis C virus NS5B polymerase inhibitors with drug-likeness and pharmacokinetic ADMET parameters predictions

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