1 A multistep docking and scoring protocol for congeneric series: Implementation on kinase DFG-out type II inhibitors José M. Granadino-Roldán 1,* , Andrés Garzón 2 , Patricia Gomez-Gutierrez 3 , Ignacio Pasamontes-Funez 4 , M. Santos Tomas 5 , Jaime Rubio-Martinez 4,* 1 Departamento de Química Física, Facultad de Ciencias Experimentales, Universidad de Jaén, Campus “Las Lagunillas” s/n, 23071, Jaén, Spain 2 Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Paseo de los Estudiantes, s/n, 02071, Albacete, Spain 3 Department of Chemical Engineering, Universitat Politecnica de Catalunya, ETSEIB. Av. Diagonal, 647, 08028 Barcelona, Spain 4 Departament de Química Física, Universitat de Barcelona (UB) and the Institut de Recerca en Quimica Teorica i Computacional (IQTCUB), Martí i Franqués 1, 08028 Barcelona, Spain 5 Department of Architecture Technology, Universitat Politecnica de Catalunya, Av. Diagonal 649, 08028 Barcelona, Spain Abstract Aim: Re-scoring of docking binding poses can significantly improve molecular docking results. Our aim was to evaluate post-processing docking protocols in order to determine the most suitable methodology for the study of the binding of congeneric compounds to protein kinases. Materials & Methods: Diverse ligand-receptor poses generated after docking were submitted to different relaxation protocols. MMPB(GB)SA approach was applied for the evaluation of the binding affinity of complexes obtained. The performance of various MMPB(GB)SA methodologies was compared. Results: The inclusion of a post-processing protocol after docking enhances the quality of the results, although the best methodology is system-dependent. Conclusion: An examination of the interactions established has allowed us to suggest useful modifications for the design of new type II inhibitors. Keywords MMPB(GB)SA, docking, B-Raf, c-Abl, p38α, scoring Acknowledgments This work was supported by Ministerio Español de Ciencia y Tecnología (project CTQ2011-29285-C02-01 and 02), the Generalitat of Catalunya (project 2014SGR1017) and the Universidad de Jaén (Ayuda a Personal Investigador de la UJA para Estancias en Otros Centros de Investigación). * E-mail: jmroldan@ujaen.es, jaime.rubio@ub.edu