Design of novel DABO derivatives as HIV-1 RT inhibitors using molecular docking, molecular dynamics simulations and ADMET properties

Zhang, Yanjun; Chen, Lu; Wang, Zhonghua; Zhu, Yiren; Jiang, Huifang; Xu, Jie; Xiong, Fei

doi:10.1080/07391102.2023.2219331

Cited by 6 publications

(3 citation statements)

References 55 publications

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“…The structures of the isoxazole compounds were optimized through energy minimization by incorporating Gasteiger–Hückel charges and a Tripos force field [ 46 , 47 ]. The maximum iteration parameter was set to 10,000 times, the energy convergence was limited to 0.05 kcal/mol, and the other values were set to default [ 48 ]. Molecular energy optimization was performed on the molecules in the training set to obtain the lowest energy conformation for each molecule, as the quality of molecular alignment is an important factor in 3D-QSAR modeling [ 49 ].…”

Section: Methodsmentioning

confidence: 99%

“…A regression analysis was performed with non-cross-validation to obtain the non-cross-validation coefficients (r 2 ), the significance test value (F), and the standard error of estimate (SEE) [ 53 ]. The parameters q 2 , F, r 2 , and SEE are the main indices used to determine the quality of 3D-QSAR models [ 54 , 55 ].To ensure that the results of the 3D-QSAR model were more informative, the following requirements for these evaluation parameters must be met: q 2 > 0.5, r 2 > 0.9, and F > 100 [ 48 , 56 ].…”

Section: Methodsmentioning

confidence: 99%

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3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists

Yan,

Yang,

Shen

et al. 2024

Molecules

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The farnesoid X receptor (FXR) has been recognized as a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). FXR agonists benefit NAFLD by modulating bile acid synthesis and transport, lipid metabolism, inflammation, and fibrosis pathways. However, there are still great challenges involved in developing safe and effective FXR agonists. To investigate the critical factors contributing to their activity on the FXR, 3D-QSAR molecular modeling was applied to a series of isoxazole derivatives, using comparative molecular field analysis (CoMFA (q2 = 0.664, r2 = 0.960, r2pred = 0.872)) and comparative molecular similarity indices analysis (CoMSIA (q2 = 0.706, r2 = 0.969, r2pred = 0.866)) models, which demonstrated strong predictive ability in our study. The contour maps generated from molecular modeling showed that the presence of hydrophobicity at the R2 group and electronegativity group at the R3 group in these compounds is crucial to their agonistic activity. A molecular dynamics (MD) simulation was carried out to further understand the binding modes and interactions between the FXR and its agonists in preclinical or clinical studies. The conformational motions of loops L: H1/H2 and L: H5/H6 in FXR–ligand binding domain (LBD) were crucial to the protein stability and agonistic activity of ligands. Hydrophobic interactions were formed between residues (such as LEU287, MET290, ALA291, HIS294, and VAL297) in helix H3 and ligands. In particular, our study found that residue ARG331 participated in salt bridges, and HIS447 participated in salt bridges and hydrogen bonds with ligands; these interactions were significant to protein–ligand binding. Eight new potent FXR agonists were designed according to our results, and their activities were predicted to be better than that of the first synthetic FXR agonist, GW4064.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists

Yan,

Yang,

Shen

et al. 2024

Molecules

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“…The crystal structure of the target protein was procured from the Protein Data Bank (www.rcsb.org, PDB ID: 7KX5), and it was analyzed and processed using the protein preparation module of SYBYL-X 2.0. [38] Based on these analysis results, the protein underwent hydrogenation, charging, side chain repair, and energy optimization with a maximum iteration number of 10000 and an energy gradient of 0.005. The original ligand molecule was eliminated to form a docking active pocket, all water molecules were removed, and other parameters were left at their default value.…”

Section: Docking Studiesmentioning

confidence: 99%

Exploring the Efficacy of Noncovalent SARS‐CoV‐2 Main Protease Inhibitors: A Computational Simulation Analysis Study

Xiong,

Zhang,

Jiang

et al. 2024

Chemistry & Biodiversity

Self Cite

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The SARS‐CoV‐2 main protease, as a key target for antiviral therapeutics, is instrumental in maintaining virus stability, facilitating translation, and enabling the virus to evade innate immunity. Our research focused on designing non‐covalent inhibitors to counteract the action of this protease. Utilizing a 3D‐QSAR model and contour map, we successfully engineered eight novel non‐covalent inhibitors. Further evaluation and comparison of these novel compounds through methodologies including molecular docking, ADMET analysis, frontier molecular orbital studies, molecular dynamics simulations, and binding free energy revealed that the inhibitors N02 and N03 demonstrated superior research performance (N02 ΔGbind = ‐206.648 kJ/mol, N03 ΔGbind = ‐185.602 kJ/mol). These findings offer insightful guidance for the further refinement of molecular structures and the development of more efficacious inhibitors. Consequently, future investigations can draw upon these findings to unearth more potent inhibitors, thereby amplifying their impact in the treatment and prevention of associated diseases.

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Towards new bioactive fluorine-containing 1,3,4-oxadiazole-amide derivatives: synthesis, antibacterial activity, molecular docking and molecular dynamics simulation study

Xiong,

Zhang,

Jiao

et al. 2024

Mol Divers

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Through the approach of molecular hybridization, this study rationally designed and synthesized new tri uoromethyl-1,3,4-oxadiazole amide derivatives, denoted as 1a-1n. The ndings reveal that these novel molecules exhibit potent inhibitory effects against various bacterial strains. Thereinto, compounds 1c, 1d, 1i, 1j and 1n, demonstrate relatively superior antimicrobial performance against B. cereus FM314, with a minimum inhibitory concentration (MIC) of 0.03907 µg/mL. Molecular docking analysis suggests the potential importance of the Ser57 and Thr125 amino acid residues in contributing to the inhibitory activity against B. cereus. The consistency of these results was further corroborated through subsequent molecular dynamics simulations and MMPBSA validations. The insights gained from this study serve to facilitate the rational design and e cient development of novel eco-friendly antimicrobial inhibitors based on the tri uoromethyl-1,3,4-oxadiazole amide scaffold.

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Design of novel DABO derivatives as HIV-1 RT inhibitors using molecular docking, molecular dynamics simulations and ADMET properties

Cited by 6 publications

References 55 publications

3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists

3D-QSAR and Molecular Dynamics Study of Isoxazole Derivatives to Identify the Structural Requirements for Farnesoid X Receptor (FXR) Agonists

Exploring the Efficacy of Noncovalent SARS‐CoV‐2 Main Protease Inhibitors: A Computational Simulation Analysis Study

Towards new bioactive fluorine-containing 1,3,4-oxadiazole-amide derivatives: synthesis, antibacterial activity, molecular docking and molecular dynamics simulation study

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