ABSTRACT
We have semi-synthesized a natural product 7-acetylhorminone from crude extract of Premna obtusifolia (Indian headache tree), which is active against colorectal cancer after probation through computational screening methods as it passed through the set parameters of pharmacokinetics (most important nonblood-brain barrier permeant) and drug likeliness (e.g., Lipinski's, Ghose's, Veber's rule) which most other phytoconstituents failed to pass combined with docking with EGFR protein which is highly upregulated in the colorectal carcinoma cell. The structure of 7-acetylhorminone was confirmed by single crystal X-ray diffraction studies and 1H NMR, 13C NMR, and COSY studies. To validate the theoretical studies, first, in vitro experiments were carried out against human colorectal carcinoma cell lines (HCT116) which revealed the potent cytotoxic efficacy of 7-acetylhorminone and verified preliminary investigation. Second, the drugability of 7-acetylhorminone interaction with serum albumin proteins (HSA and BSA) is evaluated both theoretically and experimentally via steady-state fluorescence spectroscopic studies, circular dichroism, isothermal titration calorimetry, and molecular docking. In summary, this study reveals the applicability of 7-acetylhorminone as a potent drug candidate or as a combinatorial drug against colorectal cancer.
Subject(s)
Colorectal Neoplasms , Serum Albumin, Bovine , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Serum Albumin, Bovine/metabolism , Serum Albumin, Bovine/chemistry , Drug Screening Assays, Antitumor , Biological Products/chemistry , Biological Products/pharmacology , Molecular Structure , Materials Testing , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , HCT116 Cells , Cell Proliferation/drug effects , Molecular Docking Simulation , Cell Survival/drug effects , Serum Albumin, Human/chemistry , Serum Albumin, Human/metabolismABSTRACT
Clerodin was isolated from the medicinal plant Clerodendrum infortunatum, and CSD search showed the first crystal structure of clerodin by a single-crystal X-ray diffraction study. We checked its binding potential with target proteins by docking and conducted network pharmacology analysis, ADMET analysis, in silico pathway analysis, normal mode analysis (NMA), and cytotoxic activity studies to evaluate clerodin as a potential anticancer agent. The cell viability studies of clerodin on the human breast carcinoma cell line (MCF-7) showed toxicity on MCF-7 cells but no toxicity toward normal human lymphocyte cells (HLCs). The anticancer mechanism of clerodin was validated by its enhanced capacity to produce intracellular reactive oxygen species (ROS) and to lower the reduced glutathione content in MCF-7 cells.
