Comprehensive Computational Profiling of Some New Candidate Molecules for Huntington’s Disease: Drug-Likeness, Quantum Descriptors, Molecular Docking, Molecular Dynamics Simulation and Synthetic Mechanism

Fatih İslamoğlu

doi:10.17721/fujcV13I2P31-50

Authors

Fatih İslamoğlu Recep Tayyip Erdoğan University

DOI:

https://doi.org/10.17721/fujcV13I2P31-50

Keywords:

Huntington’s disease, Computational drug design, Quantum chemical descriptors, Molecular docking, Molecular dynamics simulation

Abstract

In this study, the potential use of five novel 5,10-dihydrochromeno[5,4,3-cde]chromene-5,10-diol derivatives, which have never been synthesized before and are not reported in the literature, as active pharmaceutical ingredients for the treatment of Huntington’s disease was investigated. Huntington’s disease is a hereditary neurodegenerative disorder that causes progressive loss of nerve cells. Firstly, Boiled Egg graphs for molecular gastrointestinal (GI) absorption and blood-brain barrier (BBB) permeability and bioavailability radars for understanding the oral bioavailability suitability of molecules were generated. Then, molecular docking studies were conducted using AutoDock Vina software to predict the binding potential of molecules to biological targets, analyze interactions, and guide experimental stages in the drug discovery process against five different Homo sapiens proteins with resolution values ranging from 2.84 Å to 2.97 Å. The highest molecular docking result was obtained as 11.4 kcal/mol, a result of the interaction between 2,7-diethyl-3,8-dimethyl-5,10-dihydrochromeno[5,4,3-cde]chromene-5,10-diol (3) and the protein with PDB ID code 8T69. To further elucidate the structural and electronic features of the most promising candidate, highest occupied molecular orbital energy (E_HOMO: -0.337 a.u), lowest unoccupied molecular orbital energy (E_LUMO: 0.255 a.u), chemical potential (μ: 0.061 a.u), electron affinity (EA: -0.255 a.u), global softness (S: 1.582 a.u), global hardness (η: 0.316 a.u), ionization potential (IP: 0.377 a.u), total energy (SCF: -70.301 a.u), dipole moments (1.669 debye), electrophilicity index (ω: 0.005887658 a.u), bond angles, bond lengths, Mulliken atomic charges, and molecular electrostatic potential (MEP) were analyzed. Molecular dynamics simulations were performed to predict large-scale conformational changes. Finally, a reaction mechanism for the synthesis of the lead molecule has been proposed.

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