Computational protocol: Apaf 1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity

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Protocol publication

[…] Molecular simulations were conducted with the package Schrödinger Suite 2011 through its graphical interface Maestro . The program Macromodel , with its default force field OPLS 2005, a modified version of the OPLS-AA force field , and GB/SA water solvation conditions were used for all energetic calculations. The coordinates of WD40-deleted human Apaf-1 (Apaf-1 1–591, PDB 1Z6T, chain B) were obtained from the Protein Data Bank at Brookhaven National Laboratory. The structure of the protein was prepared using the Protein Preparation Wizard included in Maestro to remove the unused subunits as well as the solvent molecules and ligands, adding hydrogens, setting protonation states and minimizing the energy using the OPLS force field. SiteMap , , , was used to identify and score potential binding sites on the protein. The score provided by SiteMap is constructed and calibrated so that the average SiteScore for 157 investigated submicromolar sites is 1.0. Therefore, a score≥1.0 suggests a site of particular promise, while a score≤0.8 has been found to accurately distinguish between drug-binding and non-drug-binding sites. The best scored sites were used as targets for docking of the SVT016426 ligand with the program Glide XP , , . The structure of SVT016426 was built within Maestro and then it was prepared with the LigPrep application included in the software to generate ring conformers of the two stereoisomers of the compound. Eight ring conformers for each enantiomer were generated and used as input ligands for the docking at each target site. In order to ensure a good conformational sampling during the docking simulations the following settings were used: a maximum of 5000000 poses per input structure for the initial phase of docking, the extendend sampling protocol, and 50 poses for the post-docking minimization. Glide XP scores were used to rank the resulting docked poses. The interaction diagrams for the best poses were built with the Ligand Interaction Diagram application implemented in Maestro. […]

Pipeline specifications

Software tools SiteMap, Glide, LigPrep
Applications Drug design, Protein interaction analysis
Organisms Danio rerio, Rattus norvegicus
Diseases Kidney Diseases
Chemicals Cisplatin