Exploration of flexible phenylpropylurea scaffold as novel cardiac myosin activators for the treatment of systolic heart failure

Heart Failure Drug Modifies the Intrinsic Dynamics of the Pre-Power Stroke State of Cardiac Myosin

“…These bonds are particularly strong in the PPS state, where this moiety forms multiple high-occupancy interactions with D168, N711, and R712 (average occupancy >0.5, Table S3). This could explain why derivatives of OM need to retain this functional group to preserve activity. , No hydrogen bonds of comparable strength were found among the OM–myosin interactions in the NR state (Table S3). The PPS state contains also a larger number of stable OM–myosin contacts, with 11 residues found in contact with OM through their side chains for more than 70% of the simulations (average in Table S4) compared to the seven residues observed for the NR state.…”

“…Analogues were selected to sample different levels of activity while keeping their chemical structures as similar as possible to OM (Figure S4). The selected compounds, which cause a lower (group 1), similar (group 2), or higher (group 3) increase in cardiac myosin ATPase activity than OM, , were docked to the binding site, and the resulting interactions analyzed (Methods). Control calculations were also performed where OM was redocked to both myosin conformations.…”

“…OM analogues were docked to PPS and NR representative structures extracted from the OM-bound MD simulations by clustering (see above). The analogues were selected among those found in refs and as having a lower (group 1), similar (group 2), or higher (group 3) % increase in myosin ATPase activity than OM, measured for each compound with a sarcomeric assay at 10 mM. Initial ligand 3D-structures were downloaded from PubChem or, when not available, generated with the Online SMILES Translator and Structure File Generator Translator web interface () of the CACTVS system.…”

“…These bonds are particularly strong in the PPS state, where this moiety forms multiple high-occupancy interactions with D168, N711 and R712 (average occupancy > 0.5, Table S3). This could explain why derivatives of OM need to retain this functional group to preserve activity 29,30 . No hydrogen bonds of comparable strength were found among the OM-myosin interactions in the NR state (Table S3).…”

The Resurrection of Murahashi Coupling after Four Decades

“…Besides the aforementioned four reports, there were no mention of the Murahashi cross-coupling reaction in the literature for the next 23 years, while other name reactions in the area of cross-coupling have been developing into practical methodologies in organic synthesis, leading to the 2010 Nobel Prize. However, a few literature reports document the high-yielding catalyst-free reactions of organolithium reagents with aryl/alkyl halides via nucleophilic replacement pathway. − …”