Structure based pharmacophore modeling, virtual screening, molecular docking and ADMET approaches for identification of natural anti-cancer agents targeting XIAP protein

Abstract

X-linked inhibitor of apoptosis protein (XIAP) is a member of inhibitor of apoptosis protein (IAP) family responsible for neutralizing the caspases-3, caspases-7, and caspases-9. Overexpression of the protein decreased the apoptosis process in the cell and resulting development of cancer. Different types of XIAP antagonists are generally used to repair the defective apoptosis process that can eliminate carcinoma from living bodies. The chemically synthesis compounds discovered till now as XIAP inhibitors exhibiting side effects, which is making difficulties during the treatment of chemotherapy. So, the study has design to identifying new natural compounds that are able to induce apoptosis by freeing up caspases and will be low toxic. To identify natural compound, a structure-based pharmacophore model to the protein active site cavity was generated following by virtual screening, molecular docking and molecular dynamics (MD) simulation. Initially, seven hit compounds were retrieved and based on molecular docking approach four compounds has chosen for further evaluation. To confirm stability of the selected drug candidate to the target protein the MD simulation approach were employed, which confirmed stability of the three compounds. Based on the finding, three newly obtained compounds namely Caucasicoside A (ZINC77257307), Polygalaxanthone III (ZINC247950187), and MCULE-9896837409 (ZINC107434573) may serve as lead compounds to fight against the treatment of XIAP related cancer, although further evaluation through wet lab is necessary to measure the efficacy of the compounds.

Pharmacophore-Based Virtual Screening, Quantum Mechanics Calculations, and Molecular Dynamics Simulation Approaches Identified Potential Natural Antiviral Drug Candidates against MERS-CoV S1-NTD

“…Virtual screening can be defined as a cheminformatics technology that utilizes different computational techniques to screen a large number of molecules and identify the structures of interest for biological assays [ 19 ]. The accuracy of a cheminformatics model depends on the data mining process that is related to database preparation.…”

“…The SBPM can be validated through known active compounds together with inactive compounds called “decoys”. Ideally, active compounds for model validation should be selected based on experimental data [ 19 ]. Therefore, 12 experimentally active compounds against MERS-CoV S protein have been identified and retrieved from the ChEMBL database.…”

“…Receiver-operating characteristic (ROC) is a simple and useful graphical tool for evaluating the accuracy of a statistical model. The ROC curve in the virtual screening process provides information regarding the discrimination ability of the model from active to inactive (decoy) set [ 19 ]. The overall summary of the model accuracy can be calculated from the Area Under the Curve (AUC) that represents the degree of discrimination ability.…”

Compounds Identified from Marine Mangrove Plant (Avicennia alba) as Potential Antiviral Drug Candidates against WDSV, an In-Silico Approach

“…The RMSD can measure the average atomic distance of protein and help to characterize the protein [ 17 ]. The RMSD value can calculate the difference between observed value and estimated value and a value change between 1–3 Å or 0.1–0.3 nm is reasonably acceptable [ 18 , 19 ]. In our study, the RMSD value for the protein structure (Cα) residues and ligand fit protein were documented from the 100 ns simulation trajectory.…”

Spike Protein Recognizer Receptor ACE2 Targeted Identification of Potential Natural Antiviral Drug Candidates Against SARS-CoV-2

“…MD simulations provide powerful tools for the prediction of each atomic movement of protein, ligands, and physics governing interatomic interactions over a speci c time [63]. To validate the structural stability and conformational exibility protein ligands complex generated from the molecular docking study were subjected to 250 (ns) nanoseconds of MD simulations [64]. The Desmond module of Schrödinger (Release 2020-3) software package with OPLS-2005 force eld for generating system topology have been selected to simulate the complex protein-ligand structure [65].…”