Structure-activity relationships of dihydropyrimidone inhibitors against native and auto-processed human neutrophil elastase.

BACKGROUND: Human neutrophil elastase (HNE) is a key driver of systemic and cardiopulmonary inflammation. Recent studies have established the existence of a pathologically active auto-processed form of HNE with reduced binding affinity against small molecule inhibitors. METHOD: AutoDock Vina v1.2.0 and Cresset Forge v10 software were used to develop a 3D-QSAR model for a series of 47 DHPI inhibitors. Molecular Dynamics (MD) simulations were carried out using AMBER v18 to study the structure and dynamics of sc (single-chain HNE) and tcHNE (two-chain HNE). MMPBSA binding free energies of the previously reported clinical candidate BAY 85-8501 and the highly active BAY-8040 were calculated with sc and tcHNE. RESULTS: The DHPI inhibitors occupy the S1 and S2 subsites of scHNE. The robust 3D-QSAR model showed acceptable predictive and descriptive capability with regression coefficient of r2 = 0.995 and cross-validation regression coefficient q2 = 0.579 for the training set. The key descriptors of shape, hydrophobics and electrostatics were mapped to the inhibitory activity. In auto-processed tcHNE, the S1 subsite undergoes widening and disruption. All the DHPI inhibitors docked with the broadened S1'-S2' subsites of tcHNE with lower AutoDock binding affinities. The MMPBSA binding free energy of BAY-8040 with tcHNE reduced in comparison with scHNE while the clinical candidate BAY 85-8501 dissociated during MD. Thus, BAY-8040 may have lower inhibitory activity against tcHNE whereas the clinical candidate BAY 85-8501 is likely to be inactive. CONCLUSION: SAR insights gained from this study will aid the future development of inhibitors active against both forms of HNE.

Biventricular takotsubo syndrome with COVID-19 in an Asian male.

Coronavirus disease 2019 (COVID-19) has been shown to affect the cardiovascular system, and several cases of takotsubo syndrome (TTS) induced by COVID-19 have been reported. TTS predominantly affects postmenopausal women in western countries, but the prevalence in men is higher in Asian populations. It should be noted that male patients with either TTS or COVID-19 are associated with higher mortality. Despite the higher prevalence of TTS in Asian men, little is known about Asian men with TTS induced by COVID-19. This is a case report of a 60-year-old Asian male with biventricular TTS precipitated by COVID-19. He presented with acute respiratory distress syndrome, cardiogenic shock, and acute kidney injury. He required intubation, multiple vasopressors, and renal replacement therapy. The left ventricular ejection fraction was 15%, but it normalized in 5 weeks. The patient had a prolonged hospital stay in a critical condition, but was eventually discharged alive. The scarce literature about this condition in Asian male populations and the increasing number of COVID-19 cases in Asian countries highlight the rarity and importance of this case. Further studies are warranted to investigate the uneven sex distribution and outcomes of TTS triggered by COVID-19 in an Asian population. .