Conformational fingerprints in the modelling performance of MIA-QSAR: a case for SARS-CoV protease inhibitors

Abstract

Multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) has proved to be a high-performance 2D tool for drug design purposes. Nonetheless, MIA-QSAR strategy does not efficiently incorporate conformational information. Therefore, understanding the implications of including this type of data into the MIA-QSAR model, in terms of predictability and interpretability, seems a crucial task. Conformational information was included considering the optimised geometries and the docked structures of a series of disulfide compounds potentially useful as SARS-CoV protease inhibitors. The traditional analysis (based on flat-shape molecules) proved itself as the most effective technique, which means that, despite the undeniable importance of conformation for biomolecular behaviour, this type of information did not bring relevant contributions for MIA-QSAR modelling. Consequently, promising drug candidates were proposed on the basis of MIA-plot analyses, which account for PLS regression coefficients and variable importance in projection scores of the MIA-QSAR model.

Is conformation relevant for QSAR purposes? 2D Chemical representation in a 3D‐QSAR perspective

“…The most likely bioactive conformations were identified analyzing the similarity between the generated poses and the compound considered the most effective inhibitor (compound 31 ) by Wang and collaborators 11 . More details can be found elsewhere 21 …”

“…11 More details can be found elsewhere. 21 Next, the three groups of molecules were aligned using the tether tool available in the Discovery Studio Visualizer software 22 ; the congeneric center was used as the reference moiety. Figure 1 shows the resulting aligned structures.…”

Theoretical Insights into the Effect of Halogenated Substituent on the Electronic Structure and Spectroscopic Properties of the Favipiravir Tautomeric Forms and Its Implications on the Treatment of COVID-19

“…Considerable efforts have been performed in a short period of time in search of therapeutic options to treatment for infection caused by a new coronavirus -SARS-CoV-2 -, which is the cause of the disease called COVID-19. [1][2][3][4][5] Thus, researchers from all over the world have adopted as a strategy for treating COVID-19 infection attempt to inhibit two different types of known structural and non-structural proteins of the SARS-CoV-2 virus. [6][7][8][9][10] As such, the first case involves the inhibition of the main protease (abbreviated as M pro ) proteins of SARS-CoV-2.…”