DOCKING AND QUANTUM CHEMICAL INSIGHTS INTO THE ANTICANCER MECHANISMS OF MONOCHLOROACETIC AND DICHLOROACETIC ACIDS DERIVATIVES
DOI:
https://doi.org/10.11603/2312-0967.2024.4.15007Keywords:
dichloroacetate, dichloroacetic acid, dichloroacetamide, monochloroacetate, monochloroacetic acid, monochloroacetamide, quantum chemical calculations, docking simulation, antitumor activity, tumorsAbstract
The aim of the work. The present study aims to conduct the comparative quantum chemical analysis of MCA and DCA derivatives, their reactivity in interaction with protein targets, and the determination of the molecular mechanisms underlying their biological activity.
Materials and Methods. The study employed quantum chemical calculations and molecular docking to investigate synthesized compounds' electronic properties and biological interactions. Structures were optimized using DFT (B3LYP/6-311++G(d,p)) in Gaussian 09, with vibrational analyses confirming transition states. Key electronic descriptors were computed to assess reactivity. The results of quantum chemical calculations were visualized using GaussView 5.0.8. Docking simulations involved modeling glutathione-chloroacetamide conjugates at physiological pH, minimizing structures in Avogadro software, and analyzing interactions with GST (PDB ID: 11GS) using the FlexX algorithm in LeadIT. Binding interactions were visualized via BIOVIA Discovery Studio, with docking parameters validated by RMSD comparison to experimental data.
Results and Discussion. Analysis of frontier molecular orbitals and descriptors associated with their energy showed an increase in MCA activity with increasing electrophilicity. Although on individual lines, the results that fell out of this dependence may be related to their structure peculiarities. The molecular electrostatic potential analysis showed the steric hindrances’ presence due to the generous size of chlorine atoms, which reduce the possibilities for the MCA attack. The change in the Gibbs energy of the substitution reaction also indicates an easier substitution course in MCA. The molecular docking results showed the possibility of effective covalent binding to glutathione S-transferase of both MCA and DCA. However, another reason for the decrease in activity is the possibility of the DCA adduct hydrolysis with glutathione since the studied compounds do not prevent water access when binding in the active center.
Conclusions. The decrease in the DCA reactivity compared to MCA analogs is associated with steric hindrances and the chlorine atom influence in the transition state. In general, DCA's lower biological activity is associated with decreased reactivity and the possibility of joining cysteine residues to their hydrolysis products. The obtained results can become the basis for creating new targeted drugs with increased efficiency and selectivity.
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