In Silico Design of Monomolecular Drug Carriers for the Tyrosine Kinase Inhibitor Drug Imatinib Based on Calix- and Thiacalix[n]arene Host Molecules: A DFT and Molecular Dynamics Study

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• 作者：Rodrigo Galindo-Murillo ; María Eugenia Sandoval-Salinas ; Joaquín Barroso-Flores
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2014
• 出版时间：February 11, 2014
• 年：2014
• 卷：10
• 期：2
• 页码：825-834
• 全文大小：581K
• ISSN：1549-9626

文摘

The use of functionalized calix- and thia-calix[n]arenes is proposed as the basis for our in silico design of a suitable drug carrier for the tyrosine kinase inhibitor, Imatinib. Their mutual electronic properties and interaction energies, E_int, were assessed with the use of Density Functional Theory (DFT) methods under the NBODel methodology. Three structural variables for the host molecules were considered: R = {SO₃H (1), t-Bu (2), i-Pr (3), COOH (4), (CH₂)₂OH (5), (CH₂)₂NH₂ (6)}; b = {CH₂, S}; n = {5, 6, 8}, and two possible orientations for the insertion of Imatinib within the macrocycle cavity: pyridine moiety pointing inward (N1) and piperazine pointing inward (N2). In total, we explored 72 different assemblies. Initial molecular mechanics geometry optimizations with the UFF potential were undertaken for every host鈥揼uest complex, with further optimization at the B97D/6-31G(d,p) level of theory. Using the same optimized structures, Molecular Dynamics (MD) simulations were carried out on all 72 assemblies using the General Amber Force Field and the AMBER 12 MD package. Electronic parameters were fitted using the RESP method, and the complexes were run for 100 ns. Potential of mean force was obtained for the most stable systems using umbrella sampling and the Weighted Histogram Analysis Method. Calix[n]arenes families 1 and 5 (R = SO₃H and (CH₂)₂OH, respectively) with n = 6 constitute the most promising candidates to become drug carriers within our parameter space due to their more negative E_int values and increased flexibility to allow the inclusion of the drug.