IDENTIFICATION OF POTENTIAL ENZYME INHIBITOR BY MOLECULAR FRONTIER ORBITALS ANALYSIS ON PROTEIN-LIGAND COMPLEX

The use of computational resources for drug discovery is essential for selecting molecules with the intention of treating diseases. In this context, the application of Quantum Mechanics (QM) calculations stands out as a relevant tool to assist the classification of ligands in a virtual screening assay. This can be done by analyzing the energies of the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO), as well as the energy gap between HOMO and LUMO. In this study, we sought to investigate how the HOMO-LUMO gap influences the interaction between protein and ligand. For this purpose, we have selected the enzyme Vivapain 4 (VP4) from Plasmodium vivax as a model and a candidate molecule (LASSBio1804) as an inhibitor.Three systems were assembled in aqueous solvent: (a) VP4-LASSBio1804 complex; (b) apoVP4; and (c) the molecule LASSBio1804. Initially, the systems were subjected to Molecular Dynamics (MD) simulations for 100 nanoseconds (ns). Then, hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) calculations were performed for 5 femtoseconds, using the CHARMM36 force field with the NAMD2.14 software and the B3LYP 6-31G method with the ORCA software, respectively.In the QM region for system (a), it was considered the ligand and the protein residues within a distance of 5 Å from the ligand; for system (b), we selected only the amino acid residues in the enzyme's catalytic site; and for system (c), the whole ligand was included. We observed a decrease in the value of gap energy when comparing the free ligand (3.3435 eV) to the ligand in complex (0.1067 eV), which means an improvement in the electron donor-acceptor characteristic of the molecule. We also observed an approximation of the HOMO and LUMO energy values in system (a) compared to system (b). It favors the interaction through charge transfer with the enzyme. Based on the results obtained so far, we conclude that the calculation of the HOMO-LUMO energy gap of the ligand in complex with the target enzyme can be a better parameter than this calculation in isolated ligands. As a next step, we intend to apply this methodology to other protein-ligand complexes.