HIDROXYNAPHTHALENECARBOXAMIDES AND SUBSTITUTED PIPERAZINYLPROPANDIOLS, TWO NEW SERIES OF BRAF INHIBITORS. A THEORETICAL AND EXPERIMENTAL STUDY.

CAMPOS L; ANGELINA, EMILIO; GARIBOTTO F; ALVAREZ, SERGIO; VETTORAZZI, M.; ENRIZ, D

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019

UNSL

Recently we reported two new structural scaffolds as potential inhibitors of BRAF1; bothseries of compounds were studied in greater depth in the present work. Our resultsindicate that the new substituted piperazinylpropandiols derivatives evaluated here donot show significantly better activities to that previously reported for the structurechosen as starting structure. In contrast the results obtained for the other series weremore positive. We report now new hydroxynaphthalenecarboxamides with significantinhibitory activity on BRAF. In order to better understand these experimental results, wecarried out a molecular modeling study using different combined techniques. While thesimulations using simple techniques such as docking and DM simulations allowed us toexplain which the best structural scaffold, these results is do not allow to explain whycompounds with substituents in different spatial positions have similar inhibitory effects.In this sense, the use of MD/QTAIM combined calculations allow to explain in detail themolecular interactions that stabilize the different molecular complexes reported here.Another interesting contribution of this study is that the different molecular interactionsthat stabilize the complexes have been analyzed in depth. The QTAIM results indicatethat the different spatial dispositions of the substituents (ortho, meta and para) allow toestablish alternative interactions with Asp594 or with Lis483 depending on their spatialarrangement. This result is in agreement to those observed for vemurafenib anddabrafenib. This structural information is important for the design of new inhibitors withthis type of structural scaffold.