Voronoi Entropy as a Ligand Molecular Descriptor of Protein-Ligand Interactions

Sergey Shityakov; Aleksandr S Aglikov; Ekaterina V Skorb; Michael Nosonovsky

doi:10.1021/acsomega.3c07328

Voronoi Entropy as a Ligand Molecular Descriptor of Protein-Ligand Interactions

ACS Omega. 2023 Nov 27;8(48):46190-46196. doi: 10.1021/acsomega.3c07328. eCollection 2023 Dec 5.

Authors

Sergey Shityakov¹, Aleksandr S Aglikov¹, Ekaterina V Skorb¹, Michael Nosonovsky^{1

2}

Affiliations

¹ Infochemistry Scientific Center (ISC), ITMO University, 9 Lomonosova St., St. Petersburg 191002, Russia.
² College of Engineering and Applied Science, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States.

Abstract

We investigate the correlation between the Voronoi entropy (VE) of ligand molecules and their affinity to receptors to test the hypothesis that less ordered ligands have higher mobility of molecular groups and therefore a higher probability of attaching to receptors. VE of 1144 ligands is calculated using SMILES-based 2D graphs representing the molecular structure. The affinity of the ligands with the SARS-CoV-2 main protease is obtained from the BindingDB Database as half-maximal inhibitory concentration (IC₅₀) data. The VE distribution is close to the Gaussian, 0.4 ≤ S_v ≤ 1.66, and a strong correlation with IC₅₀ is found, IC₅₀ = -275 S_v + 613 nM, indicating the correlation between ligand complexity and affinity. On the contrary, the Shannon entropy (SE) descriptor failed to provide enough evidence to reject the null hypothesis (p-value > 0.05), indicating that the spatial arrangement of atoms is crucial for molecular mobility and binding.