By: Hamdullah Khadim Sheikh, Jose M Padron, Tanzila Arshad, Uzma Habib, Shahnila Jamil, Haroon Khan and Khurshid Ayub
Keywords: Computer-aided drug design, ?-tubulin, ADMET, molecular dynamics simulations, paclitaxel, QSPR modeling.
DOI : 10.36721/PJPS.2024.37.5.REG.949-959.1
Abstract: We report a new scoring method for rating the performance of ligands on same protein, using their extensive dynamic flexibility properties, binding with protein, and impact on receptor protein. Based on molecular dynamics (MD), this method is more accurate than single-point energy calculations. This method identified an ideal FDA-approved drug as ?-tubulin microtubule inhibitor with improved attributes compared to commercial microtubule disassembly inhibitor, Paclitaxel (PTX). We started with virtual screening (VS) of FDA-approved drugs inside PTX’s binding pocket (A) of human ?-tubulin protein. Screened ligands (>80% score) were evaluated for non-permeation through blood-brain barrier (BBB) as targets were body cancers, gastrointestinal absorption, Lipinski, non-efflux from central nervous system (CNS) by p-glycoprotein (Pgp) and ADMET analysis. This identified FDA-approved Naloxegol drug with superior attributes compared to PTX. Pocket (A) specific docking of chain length variable derivatives of Naloxegol gave docked poses that underwent MD run to give a range of properties and their descriptors (RMSD, RMSF, RoG, H-bonds, hydrophobic interaction, and SASA). QSPR validated that MD properties dependent upon [-CH2-CH2-O-]n=0-7 chain length of Naloxegol. MD data underwent normalization, PCA analysis, and scoring against PTX. One Naloxegol derivative scored higher than PTX as a potential microtubule disassembly inhibitor.
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