Systems and methods of selecting compounds with reduced risk of cardiotoxicity
A technology for cardiotoxicity and compounds, applied in the field of compound processor implementation systems, which can solve the problems of not providing structural recombination, short duration of MD simulation, lack of accurate atomic-level methods for cardiotoxicity problems, etc.
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example 1
[0672] 7.1 Example 1: Recombination / homologous protein simulation
[0673] The methods disclosed herein can be performed as described in Examples 1-15 when applied to potassium ion channels.
[0674] Recombination of hERG1 channel proteins and homologous protein simulations were performed as previously described (Durdagi et al., 2012, "Modeling of Open, Closed, and Open-Inactivated States of the HERG1 Channel: Structural Mechanisms of the State-Dependent Drug Binding," J . Chem. Inf. Model, 52, 2760-2774). Figure 4 and Figure 5 present the molecular models of hERG1 monomeric subunits and hERG1 tetramers, respectively.
[0675] In short, stored in K + Homology modeling of portions of the hERG1 structure with known crystal structures in the channel used target-template sequence alignment performed by the ClustalW algorithm (Thompson et al., 1994, "Improving the Sensitivity of Progressive Multiple Sequence Alignment Through Sequence Weighting, Position-Specific Gap Penalties ...
example 2
[0679] 7.2 Example 2: Compound (ligand) preparation
[0680] The 2D information of the compound (ligand) was translated into 3D using the software Molecular Operating Environment (MOE) (http: / / www.chemcomp.com / press_releases / 2010-11-30.htm) from the Chemical Computing Group (CCG) representative structure. MOEs also generate variants of the same ligand with different tautomeric, stereochemical, and ionization properties. All resulting structures were conformationally relaxed using the energy minimization protocol included in the MOE.
[0681] Alternatively or additionally, from Kit software LigPrep ( Release2013-2: LigPrep, version 2.7, LLC, New York, NY, 2013) can be used to translate 2D information of compounds (ligands) into 3D representative structures. LigPrep can also be used to generate variants of the same ligand with different tautomeric, stereochemical, and ionizing properties. All resulting structures can be conformationally relaxed using the energy minimizati...
example 3
[0682] 7.3 Example 3: Molecular Dynamics Simulation
[0683] Use of NAMD (not (only) another molecular dynamics program) in a Molecular Operating Environment (MOE) (Phillips et al., 2005, "Scalable Molecular Dynamics with NAMD," J. Comput. Chem., 26, 1781-1802; Kalé et al., 1999, "NAMD2: Greater Scalability for Parallel Molecular Dynamics," J. Comp. Phys. 151, 283-312) performed all atomic MD simulations of the selected models.
[0684] A perhydro AMBER99SB force field was used for proteins (Hornak et al., 2006, "Comparison of Multiple Amber Force Fields and Development of Improved Protein Backbone Parameters," Proteins 65, 712-725) and a generalized AMBER force field for ligands. ; GAFF) (Wang et al., 2004, "Development and Testing of a General Amber Force Field," J.Comput.Chem.25, 1157-1174) performed MD simulations at 300K with physiological pH (pH 7) and 1 standard atmosphere .
[0685] Similar to previous MD simulations of the K channel (Chivian et al., 2006, "Homology ...
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