In silico inhibition of SARS-CoV-2 and CHIKV by phenol and chromone derivatives

Abstract

In a new context, such as climate change and the spread of endemic tropical diseases, such as the recent COVID-19 pandemic, misinformation and non-adherence to the scientific method can exacerbate the socio-economic impact of the situation, which justifies the relevance of new ways of streamlining research in this area. The traditional method of drug development is trial and error, which is time-consuming and expensive, and therefore not ideal in this new scenario of global health. One way to narrow down and screen potential drugs, streamline the process and reduce costs is through the computational chemistry. With this in mind, the aim of this thesis was to find a group of molecules capable of inhibiting the SARS-CoV-2 and Chikungunya viruses. Thus, the first work consisted in the use of a group of molecules reported in the literature, derivatives of phenol and chromones from Daldinia sp., for the inhibition of the spike glycoprotein of SARS-CoV-2, important for the viral entry into the cells. Based on the binding affinity, a molecular docking simulation was perfomed to obtain the lowest energy derivative (Der4), the PAINS and interferents were filtered out for molecular modelling, yielding 557 hits with binding affinities between -7 kcal/mol and -13 kcal/mol, from which the one with the highest synthetic accessibility (hit 48, 80%) and the one with the lowest energy (hit 250, -13 kcal/mol) were selected, a new docking simulation was perfomed, then a molecular dynamics and ADMET. Both presented properties indicating a good inhibitory action in important residues of the spike glycoprotein as well as the viability to be an oral drug, despite the difficulty to synthesise. After the first work, the second is the evaluation of the same group of molecules from Daldinia sp. for the inhibition of the Chikungunya virus (CHIKV), the targets chosen being the non-structural proteins nsP2 and nsP3. The docking results showed that all the derivatives have high binding energy with nsP2 and low with nsP3, with results below -6,2 kcal/mol, with all major residues having strong to moderate interactions, highlighted for Der9 to Der12. Despite the low energy, the ADMET results show some drawbacks of these derivatives as a drugs, with high probability of producing toxic metabolites, nevertheless Der8 is highlighted due to good binding energy, good medicinal descriptors and has already been reported as an inhibitor of Zika virus in vitro. Therefore, the selected and modelled molecules are viable for the next steps for drug development.