Computational Identification of Druggable Bioactive Compounds from Catharanthus roseus and Avicennia marina against Colorectal Cancer by Targeting Thymidylate Synthase

Abstract

Colorectal cancer (CRC) is the second most common cause of death worldwide, affecting approximately 1.9 million individuals in 2020. Therapeutics of the disease are not yet available and discovering a novel anticancer drug candidate against the disease is an urgent need. Thymidylate synthase (TS) is an important enzyme and prime precursor for DNA biosynthesis that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) that has emerged as a novel drug target against the disease. Elevated expression of TS in proliferating cells promotes oncogenesis as well as CRC. Therefore, this study aimed to identify potential natural anticancer agents that can inhibit the activity of the TS protein, subsequently blocking the progression of colorectal cancer. Initially, molecular docking was implied on 63 natural compounds identified from Catharanthus roseus and Avicennia marina to evaluate their binding affinity to the desired protein. Subsequently, molecular dynamics (MD) simulation, ADME (Absorption, Distribution, Metabolism, and Excretion), toxicity, and quantum chemical-based DFT (density-functional theory) approaches were applied to evaluate the efficacy of the selected compounds. Molecular docking analysis initially identified four compounds (PubChem CID: 5281349, CID: 102004710, CID: 11969465, CID: 198912) that have better binding affinity to the target protein. The ADME and toxicity properties indicated good pharmacokinetics (PK) and toxicity ability of the selected compounds. Additionally, the quantum chemical calculation of the selected molecules found low chemical reactivity indicating the bioactivity of the drug candidate. The global descriptor and HOMO-LUMO energy gap values indicated a satisfactory and remarkable profile of the selected molecules. Furthermore, MD simulations of the compounds identified better binding stability of the compounds to the desired protein. To sum up, the phytoconstituents from two plants showed better anticancer activity against TS protein that can be further developed as an anti-CRC drug.

Structural-Guided Identification of Small Molecule Inhibitor of UHRF1 Methyltransferase Activity

“…The study showed that chicoric acid formed significant interactions with Asp469 while the interaction with nystose is very low. Furthermore, the study utilized molecular dynamics simulation to analyze the protein-ligand complex stability ( Islam et al, 2022 ). Also, MD simulation calculates the RMSD values to confirm the interaction stability and rigidity of the compounds with the target protein ( Liu et al, 2017 ).…”

A study on DNA methylation modifying natural compounds identified EGCG for induction of IFI16 gene expression related to the innate immune response in cancer cells

“…The 5-aza-dc was selected as a positive control for DNMT proteins. The proteins were preprocessed using Biovia Discovery Studio visualizer (3ds.com/products-services/biovia/products/molecular-modeling-simulation/biovia-discovery-studio/visualization/) version (16.1.0) ( 41 ). For molecular docking, PyRX software version 0.8 ( ) ( 42 ) was used via integrated Open Bable to optimize ligands.…”

“…Autodock wizards were used to create maximum grid box dimensions. After running docking via Run Autodock in Vina wizard, the ligand in a complex with the protein was visualized using Biovia Discovery Studio visualizer version (16.1.0) ( 41 ).…”

Dostarlimab as a Miracle Drug: Rising Hope against Cancer Treatment

“…Immuno-oncology is the newest field of research in this area and its scope and full potential are yet to be explored. As part of immunotherapy, specific parts of the patient’s immune system are used to treat a range of diseases, including cancer and mostly solid tumors [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Cancer immunotherapy aims to re-activate the immune system, which has been suppressed by tumor cells in numerous ways.…”