Isolation optimisation, synthesis, molecular docking and <i>in silico</i> ADMET studies of lantadene a and its derivatives

Kumar, Sunita; Hooda, Ajay; Sharma, Ankesh; Bansal, Sumit; Monga, Jitender; Chauhan, Monika; Sharma, Manu

doi:10.1080/14786419.2020.1752204

Cited by 8 publications

(8 citation statements)

References 12 publications

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“…We have chosen the dataset of recently synthesised and evaluated Lantadenes (1-4) and their modified analogues (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) from the published report as indicated in Figure 1. 21…”

Section: Datasetmentioning

confidence: 99%

“…Two-dimensional (2D) structures of all the test compounds i,e Lantadene analogues (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and Bortezomib were sketched using Chem-Draw Ultra 8.0 and converted into their corresponding three-dimensional (3D) structures with the help of VLife converter module. All the molecules were energetically, geometrically minimized and optimized with default settings up to the rms gradient of 0.01 using Merck Molecular Force Field (MMFF).…”

Section: Ligand Standardizationmentioning

confidence: 99%

“…Caco-2 permeability represents an important parameter to determine the oral absorption and permeability in early phases of drug design with optimal value higher than -5.15 cm/s. 34 All the modified Lantadene analogues (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) showed the permeability values in range from -5.01 to -5.25 cm/s and the lead analogue showed comparable permeability with its highest value -5.17 cm/s. In addition, all the compounds qualified HIA% with value ≥30% a key parameter for oral bioavailability absorption related to the permeation of compounds through biological membrane under the influence of physicochemical characteristics.…”

Section: P-120mentioning

confidence: 99%

“…38 30,39 Drug induced toxicity is a major cause for drug withdrawal from the market and remain a key concern for the development of novel molecules. 40 All the compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) indicted negative test for H-HT and AMES test. Except for compounds 5-8 and 12 all the analogues showed non-toxicity towards hERG.…”

Section: P-120mentioning

confidence: 99%

“…14 Further, number of existing reports on Lantadenes and their derivatives with modifications at ring A and D showed marked anti-tumor and anti-inflammation potential via downregulation of NF-κB, c-Jun, Bcl-2,and inhibiting Akt protein and NF-κB activation. [15][16][17][18][19][20] Recent work on Lantadene scaffold described the synthesis of various Lantadene modified analogues figure1 and their evaluation as antitumor potential & inhibition of tumor necrosis factor-alpha-induced (TNF-α induced) NF-κB activation using lung adenocarcinoma A549 cell line. These analogues displayed significant antiproliferative activity and provided us with 10 and 12 as promising candidates against lung cancer.…”

Section: Introductionmentioning

confidence: 99%

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Lantadenes Targeting NF-ΚB in Cancer: Molecular Docking and ADMET Predictions

Sharma

Aggarwal

et al. 2021

Int J Life Sci Pharm Res

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Natural products and their scaffolds encompasses an array of molecular entities as starting points for drug designing and discovery. In the past two decades, phytochemically driven Lantadenes and their modified analogues have attracted lots of attention due to their tumor necrosis factor-α induced nuclear factor-kappa B inhibition and consequently their promising anticancer potential. Earlier reports described the synthesis of esters at C-3 and C-22 of pentacyclic triterpenoid Lantadene, and their evaluation to inhibit tumor necrosis factor-α induced nuclear factor-kappa B along with cytotoxicity against A549 lung cancer cells. In the modern drug discovery process, molecular docking have become an integral part of drug design. Combination of computational platforms and experimental strategies have allowed many successful stories in the discovery of new structure-based or mechanism drugs. Thus as a continuation of our research concerning Lantadenes and their significance, present study has been undertaken to predict binding mode, pharmacokinetic and drug likeness using Vlife MDS Biopredicta and ADMETlab tools. In silico inspired grip docking approach was utilized to estimate binding interactions of all the optimized Lantadenes and their modified ester against nuclear factor-kappa B receptor (PDB ID: 1LE9). In addition, all the compounds were screened for pharmacokinetic profile and drug likeness as an important consideration for the selection of compounds with desirable prosperities using ADMETlab tools. Ligand-receptor analysis revealed Lantadene parent nuclei and their modified analogues as potent inhibitors of nuclear factor-kappa B receptor based on binding energy (-21.16 to-42.56 kcal/mol), number of interactions and bond length. Furthermore, most of the analogues were found to have good ADMET profiles. Cumulative computational analyses provided the lead Lantadene analogue 10 and can be considered as a potential candidate for detailed mechanistic studies against lung cancer.

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