Key result
Computational screening and de novo design identified 6 novel ligands targeting Cardiac Troponin C with binding energies and complex stabilities comparable to or better than bepridil.
Computational screening and molecular dynamics identified 6 novel ligands with binding affinities to cardiac troponin C comparable to or better than bepridil, offering potential starting points for heart failure drug development.
Cardiac troponin C (cTnC) is the Ca²⁺ dependent switch for contraction in heart muscle making it a potential target for drug research in the therapy of heart failure. Calcium binding on Troponin C (TnC) triggers a series of conformational changes exposing a hydrophobic pocket in the N-domain of TnC (cNTnC), which leads to force generation. Mutations and acidic pH have been related to altering the sensitivity of TnC affecting the efficiency of the heart. Bepridil, identified as a calcium sensitizer to TnC, has been experimentally found to bind to the N-domain pocket of TnC but with negative cooperativity. Screening and de novo design were carried out using LUDI and AUTOLUDI programs in this work to identify and design potential ligands that can bind to the hydrophobic pocket of TnC. Two docking centers and multiple searching radii including 5 Å, 5.5 Å, 6 Å, 6.5 Å, 7.0 Å and 7.5 Å were used in LUDI to screen the ZINC database. Based on the LUDI docking results, 8 molecules were identified from the database with good potential to bind into the binding pocket and they were used as template molecules to generate a series of new molecules by AUTOLUDI design. Out of all the newly-designed molecules, 14 new ligands were recognized to be potential ligands that can bind and fit well into the binding pocket. These molecules can be used as starting molecules to develop TnC ligands. The binding stability and binding affinity of these molecules to the protein was further analyzed by molecular dynamics simulations. The results show that the binding energies, interactions and complex stabilities of 6 ligands are comparable to or better than bepridil.
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Varughese et al. (2011) studied Heart failure. Novel ligands designed via LUDI and AUTOLUDI vs. Bepridil was evaluated on Binding stability and affinity. Computational screening and de novo design identified 6 novel ligands targeting Cardiac Troponin C with binding energies and complex stabilities comparable to or better than bepridil.
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