Pharmacophore-Based Virtual Screening and In-Silico Explorations of Biomolecules (Curcumin Derivatives) of Curcuma longa as Potential Lead Inhibitors of ERBB and VEGFR-2 for the Treatment of Colorectal Cancer.

The newly FDA-approved drug, Axitinib, is an effective therapy against RTKs, but it possesses severe adverse effects like hypertension, stomatitis, and dose-dependent toxicity. In order to ameliorate Axitinib's downsides, the current study is expedited to search for energetically stable and optimized pharmacophore features of 14 curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) derivatives. The rationale behind the selection of curcumin derivatives is their reported anti-angiogenic and anti-cancer properties. Furthermore, they possessed a low molecular weight and a low toxicity profile. In the current investigation, the pharmacophore model-based drug design, facilitates the filtering of curcumin derivatives as VEGFR2 interfacial inhibitors. Initially, the Axitinib scaffold was used to build a pharmacophore query model against which curcumin derivatives were screened. Then, top hits from pharmacophore virtual screening were subjected to in-depth computational studies such as molecular docking, density functional theory (DFT) studies, molecular dynamics (MD) simulations, and ADMET property prediction. The findings of the current investigation revealed the substantial chemical reactivity of the compounds. Specifically, compounds S8, S11, and S14 produced potential molecular interactions against all four selected protein kinases. Docking scores of -41.48 and -29.88 kJ/mol for compounds S8 against VEGFR1 and VEGFR3, respectively, were excellent. Whereas compounds S11 and S14 demonstrated the highest inhibitory potential against ERBB and VEGFR2, with docking scores of -37.92 and -38.5 kJ/mol against ERBB and -41.2 and -46.5 kJ/mol against VEGFR-2, respectively. The results of the molecular docking studies were further correlated with the molecular dynamics simulation studies. Moreover, HYDE energy was calculated through SeeSAR analysis, and the safety profile of the compounds was predicted through ADME studies.

Computational Investigation of 1, 3, 4 Oxadiazole Derivatives as Lead Inhibitors of VEGFR 2 in Comparison with EGFR: Density Functional Theory, Molecular Docking and Molecular Dynamics Simulation Studies.

Vascular endothelial growth factor (VEGF) is an angiogenic factor involved in tumor growth and metastasis. Gremlin has been proposed as a novel therapeutic pathway for the treatment of renal inflammatory diseases, acting via VEGFR 2 receptor. To date, most FDA-approved tyrosine kinase (TK) inhibitors have been reported as dual inhibitors of EGFR and VEGFR 2. The aim of the present study was to find the potent and selective inhibitor of VEGFR 2 specifically for the treatment of renal cancer. Fourteen previously identified anti-inflammatory compounds i.e., 1, 3, 4 oxadiazoles derivatives by our own group were selected for their anti-cancer potential, targeting the tyrosine kinase (TK) domain of VEGFR2 and EGFR. A detailed virtual screening-based study was designed viz density functional theory (DFT) study to find the compounds' stability and reactivity, molecular docking for estimating binding affinity, SeeSAR analysis and molecular dynamic simulations to confirm protein ligand complex stability and ADMET properties to find the pharmacokinetic profile of all compounds. The DFT results suggested that among all the derivatives, the 7g, 7j, and 7l were chemically reactive and stable derivatives. The optimized structures obtained from the DFTs were further selected for molecular docking, and the results suggested that 7g, 7j and 7l derivatives as the best inhibitors of VEGFR 2 with binding energy values -46.32, -48.89 and -45.01 kJ/mol. The Estimated inhibition constant (IC50) of hit compound 7j (0.009 µM) and simulation studies of its complexes confirms its high potency and best inhibitor of VEGFR2. All the derivatives were also docked with EGFR, where they showed weak binding energies and poor interactions, important compound 7g, 7j and 7i exhibited binding energy of -31.01, -33.23 and -34.19 kJ/mol respectively. Furthermore, the anticancer potential of the derivatives was confirmed by cell viability (MTT) assay using breast cancer and cervical cancer cell lines. At the end, the results of ADMET studies confirmed these derivatives as drug like candidates. Conclusively, the current study suggested substituted oxadiazoles as the potential anticancer compounds which exhibited more selectivity towards VEGFR2 in comparison to EGFR. Therefore, the identified lead molecules can be used for the synthesis of more potent derivatives of VEGFR2, along with extensive in vitro and in vivo experiments, that can be used to treat various cancers, especially renal cancers, and to prevent angiogenesis due to aberrant expression of VEGFR2.

In Silico Prospects and Therapeutic Applications of Ouabagenin and Hydroxylated Corticosteroid Analogues in the Treatment of Lung Cancer.

Lung cancer is the second most prevalent carcinoma around the world, and about 80% of patients are of non-small cell lung cancer (NS-CLC). Epidermal growth factor receptor (EGFR) is the most expressed protein kinases in lung cancer and hence can be used in target-related anti-cancer therapy. Here, computational approach is used for the exploration of the anti-cancer potential of new steroid derivatives as previously no in vitro data was available for them. Initially, DFT calculations of all compounds were determined to analyze the electronic density of optimized structures. The HOMO and LUMO orbital analysis of all derivatives was analyzed, to investigate the reactivity of compounds. Afterwards, optimized structures were used for molecular docking studies in which all ouabagenin derivatives were docked within the EGFR active site using MOE software. Moreover, anti-cancer potential of selected derivatives was evaluated on the basis of binding interactions with three anti-cancer proteins. The binding scores of these compounds were compared with the FDA-approved drug, i.e., gefitinib. The findings of current study suggested that selected derivatives exhibited significant inhibiting potential of anti-cancer proteins and EGFR. Particularly, compound OD3 is the potent inhibitor of anti-cancer and EGFR protein with the highest binding energies. These novel steroidal derivatives are subjected to in silico analysis for the first time against lung cancer. These compounds possess potential anti-cancerous properties and can be explored further for in vitro and in vivo studies.