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We have developed two ligand and receptor-based computational approaches to study the physicochemical properties relevant to the biological activity of vasopressin V2 receptor (V2R) antagonist and eventually to predict the expected binding mode to V2R. The obtained Quantitative Structure Activity Relationship (QSAR) model showed a correlation of the antagonist activity with the hydration energy (EH 2 O) , the polarizability (P) and the calculated partial charge on atom N7 (q6) of the common substructure. The rst two descriptors showed a positive contribution to antagonist activity, while the third one had a negative contribution. V2R was modeled and further relaxed on a 1-palmitoyl-2-oleoyl-snglycero-3-phosphocoline (POPC) membrane by molecular dynamics simulations. The receptor antagonist complexes were guessed by molecular docking, and the stability of the most relevant structures were also evaluated by molecular dynamics simulations. As a result, amino acid residues Q96, W99, F105, K116, F178, A194, F307, and M311 were identi ed with the probably most relevant antagonist-receptor interactions on the studied complexes. The proposed QSAR model could explain the molecular properties relevant to the antagonist activity. The contributions to the antagonist-receptor interaction appeared also in agreement with the binding mode of the complexes obtained by molecular docking and Molecular Dynamics. These models will be used in further studies to look for new V2R potential antagonist molecules.

We have developed two ligand and receptor-based computational approaches to study the physicochemical properties relevant to the biological activity of vasopressin V2 receptor (V2R) antagonist and eventually to predict the expected binding mode to V2R. The obtained Quantitative Structure Activity Relationship (QSAR) model showed a correlation of the antagonist activity with the hydration energy (EH2O) , the polarizability (P) and the calculated partial charge on atom N7 (q6) of the common substructure. The first two descriptors showed a positive contribution to antagonist activity, while the third one had a negative contribution. V2R was modeled and further relaxed on a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocoline (POPC) membrane by molecular dynamics simulations. The receptor antagonist complexes were guessed by molecular docking, and the stability of the most relevant structures were also evaluated by molecular dynamics simulations. As a result, amino acid residues Q96, W99, F105, K116, F178, A194, F307, and M311 were identified with the probably most relevant antagonist-receptor interactions on the studied complexes. The proposed QSAR model could explain the molecular properties relevant to the antagonist activity. The contributions to the antagonist-receptor interaction appeared also in agreement with the binding mode of the complexes obtained by molecular docking and Molecular Dynamics. These models will be used in further studies to look for new V2R potential antagonist molecules.

Phytocompounds xanthatin and 8-epi-xanthatin, obtained from Xanthium chinese Mill, showed antitumoral activity in vitro, related to the microtubules destabilizing properties of these phytocompounds. However, the exact binding pocket on tubulin of these isomers remains unknown. The aim of this work is, to develop a comprehensive computational strategy to understand and eventually predict the structure-activity relationship of xanthatin and 8-epi-xanthatin, with the destabilizingantimitotic binding domain in tubulin heterodimer and to propose a putative binding site for these phytocompounds into the microtubule destabilizing agents binding sites in the tubulin heterodimer. A molecular docking was performed using the xanthanolides conformers as ligands and several tubulin structures obtained from the Protein Data Bank as receptor. The xanthanolides-tubulin complexes were energy minimized by molecular dynamics simulations at vacuum and their stability was evaluated by solvated molecular dynamics simulations during 100 ns. Xanthanolides showed higher stability into the colchicine and pironetin binding sites, whit a greater a nity for the former. In addition, the xanthanolides and non-classical colchicine binding site inhibitors share a high structural similarity.

Phytocompounds xanthatin and 8-epi-xanthatin, obtained from Xanthium chinese Mill, showed antitumoral activity in vitro, related to the microtubules destabilizing properties of these phytocompounds. However, the exact binding pocket on tubulin of these isomers remains unknown. The aim of this work is, to develop a comprehensive computational strategy to understand and eventually predict the structure-activity relationship of xanthatin and 8-epi-xanthatin, with the destabilizing-antimitotic binding domain in tubulin heterodimer and to propose a putative binding site for these phytocompounds into the microtubule destabilizing agents binding sites in the tubulin heterodimer. A molecular docking was performed using the xanthanolides conformers as ligands and several tubulin structures obtained from the Protein Data Bank as receptor. The xanthanolides-tubulin complexes were energy minimized by molecular dynamics simulations at vacuum and their stability was evaluated by solvated molecular dynamics simulations during 100 ns. Xanthanolides showed higher stability into the colchicine and pironetin binding sites, whit a greater affinity for the former. In addition, the xanthanolides and non-classical colchicine binding site inhibitors share a high structural similarity.