Estudo computacional de moléculas com potencial inativante do SARS-CoV-2

Abstract

The 3CL-protease (3CLpro) is a crucial therapeutic target against SARS-CoV-2 because it is a non-structural protein linked to viral replication and highly conserved among coronaviruses. This work evaluated in silico, through 1 microsecond molecular dynamics (MD) simulations, the inhibitory activity mecha- nisms and molecular recognition of the 3CL homodimer against two classes of lig-ands: coumarin derivatives (esters of 4-esculetinocarboxylic acid) and copper sulfide nanoparticles functionalized with penicillamine. Coumarin bindings alter the enzy-matic structure in distinct ways; Ethyl 5,6-dihydroxy-2-oxo-1a,7b-dihydrooxyrene[2,3- c]chromene-7b-carboxylate promoted asymmetry at the quaternary interface with loss of dimer compaction, while Ethyl 1,1-dichloro-7,8-dihydroxy-2-oxo-1a,7b-dihy- dro-1H-cyclopropa[c]chromene-7b-carboxylate exhibited a larger thermodynamic layer and conformational stability, despite undergoing partial dissociation followed by spontaneous reassociation. However, a hydrogen bond analysis indicated that the coumarin results fluctuate in the structure without a specific layer. In contrast, the nanoparticles showed a specificity of stereoselective chiral recognition at the dimer- ization interface. The nanoparticle with D-penicillamine severely induced and strengthened attractive interactions between monomers, stabilizing the enzyme. On the other hand, the nanoparticle with L-penicillamine caused allosteric destabilization with weakening of intermolecular forces at the dimer interface. The nanoparticle with L-penicillamine distributed significant isolating bonds, consolidating itself as the chiral vector with the greatest efficiency and dynamic biocompatibility. It is concluded that nanoparticles, especially the levorotatory form, exhibit strong allosteric inhibitory po- tential of 3CLpro, validating the robustness of the methodology for replication in otherpathogenic systems.