In Silico Study on the Interactions, Molecular Docking, Dynamics and Simulation of Potential Compounds from Withania somnifera (L.) Dunal Root against Cancer by Targeting KAT6A

Abstract

Cancer is characterized by the abnormal development of cells that divide in an uncontrolled manner and further take over the body and destroy the normal cells of the body. Although several therapies are practiced, the demand and need for new therapeutic agents are ever-increasing because of issues with the safety, efficacy and efficiency of old drugs. Several plant-based therapeutics are being used for treatment, either as conjugates with existing drugs or as standalone formulations. Withania somnifera (L.) Dunal is a highly studied medicinal plant which is known to possess immunomodulatory activity as well as anticancer properties. The pivotal role of KAT6A in major cellular pathways and its oncogenic nature make it an important target in cancer treatment. Based on the literature and curated datasets, twenty-six compounds from the root of W. somnifera and a standard inhibitor were docked with the target KAT6A using Autodock vina. The compounds and the inhibitor complexes were subjected to molecular dynamics simulation (50 ns) using Desmond to understand the stability and interactions. The top compounds (based on the docking score of less than −8.5 kcal/mol) were evaluated in comparison to the inhibitor. Based on interactions at ARG655, LEU686, GLN760, ARG660, LEU689 and LYS763 amino acids with the inhibitor WM-8014, the compounds from W. somnifera were evaluated. Withanolide D, Withasomniferol C, Withanolide E, 27-Hydroxywithanone, Withanolide G, Withasomniferol B and Sitoindoside IX showed high stability with the residues of interest. The cell viability of human breast cancer MCF-7 cells was evaluated by treating them with W. Somnifera root extract using an MTT assay, which showed inhibitory activity with an IC50 value of 45 µg/mL. The data from the study support the traditional practice of W. somnifera as an anticancer herb.

Pharmacoinformatics-Based Approach for Uncovering the Quorum-Quenching Activity of Phytocompounds against the Oral Pathogen, Streptococcus mutans

“…Computational drug discovery studies evaluate the binding of ligands with the target protein, but the agonist or antagonistic effect of ligands on the target protein is only validated through in vitro and in vivo experiments [ 42 , 43 ]. In the current study, based on an initial screening of 110 compounds using AutoDock, 17 high binders were selected that were found to bind with all the target proteins efficiently.…”

Exploring the therapeutic mechanism of potential phytocompounds from Kalanchoe pinnata in the treatment of diabetes mellitus by integrating network pharmacology, molecular docking and simulation approach

“…The protein preparation module in Discovery Studio 2018 was employed to optimize the crystal structures for docking investigations. Co-factors, hetero-atoms, and water molecules were removed to improve the structure, and the missing atom, hydrogen bond, and charges were computed ( Yaraguppi et al, 2022 ), ( Deshpande et al, 2023 ). Further Autodock tool was used to perform protein–ligand interaction and binding energy was determined.…”

Cellular Mechanistic Considerations on Cytotoxic Mode of Action of Phosphino Ru(II) and Ir(III) Complexes

“…[8][9][10][11] Although currently used anticancer drugs show remarkable effects during initial treatment, a large majority of patients develop resistance as treatment proceeds. [12][13][14] Currently, half-sandwich organometallic complexes of such metal ions as Ir(III) and Ru(II) are of great interest (Scheme 1). [15,16,17] They have a stable structure with various ligands and exhibit excellent anticancer activity.…”

“…Even though several therapies are practiced, the need for new anticancer agents is ever‐increasing because of issues with the safety, efficacy, efficiency, bioavailability, and toxicity of old drugs such as cisplatin [8–11] . Although currently used anticancer drugs show remarkable effects during initial treatment, a large majority of patients develop resistance as treatment proceeds [12–14] …”