LEDGINs: relationship between conformational and inhibitory properties

RIBONE, S. R.; QUEVEDO, M. A.; MADRID, M.; PIERINI, A.

Santiago de Chile

Congreso; 10th Congress of the World Association of Theoretical and Computational Chemists; 2014

World Association of Theoretical and Computational Chemists

Among new therapeutic targets for the treatment of the Human Immunodeficiency Virus (HIV), viral integrase (IN) has drawn significant attention towards the inhibition of its interaction with cellular cofactors. Among them, the lens epithelium-derived growth factor (LEDGF) forms a preintegration complex (PIC) with IN, facilitating its interaction with the nuclear chromatin. Consequently, inhibitors able to block the IN-LEDGF recognition are being developed as potent anti HIV agents, known as ?LEDGINs?. The crystallographic structures of the LEDGF-IN complex have paved the way to the application of structure-based drug design techniques of new LEDGINs. Although diverse chemical entities have been designed, with their corresponding anti HIV potencies being determined, classical studies aimed to explore the correlation between their chemical structure and corresponding biological activity have failed to establishing conclusions useful for the design of new inhibitors [1a-b]. In this work, classical molecular modeling tools (docking and molecular dynamics) were combined with exhaustive conformational sampling techniques, in order to study the correlation between the inhibitory potencies of 12 LEDGINs (2-(quinolin-3-yl) and 4-(quinolin-3-yl)-acetic acids derivatives) with the energies required to adopt the bioactive conformation. For these purposes, conformation sampling and docking software designed by OpenEye Scientific Software were employed [2a-b]. Conclusions derived from docking studies were further aided by molecular dynamics simulations and energies of binding analyses. As can be seen in Table 1, the most potent inhibitors exhibited a marked conformational pre-organization (i.e. low number of conformers at low energy windows), which was further aided by significant electrostatic interactions with IN (data not shown). This demonstrates that the complementarity with the receptor (measured as the interaction energy) is not the only structural factor determining the biological activity, but also the molecular flexibility of the LEDGIN and its ability to adopt the bioactive conformation at low energy windows should be addressed as part of the screening of potent LEDGINs.