Role of interaction mode of phenanthrene derivatives as selective PDE5 inhibitors using molecular dynamics simulations and quantum chemical calculations.

Phosphodiesterase type 5 (PDE5) inhibitors play a crucial role in blocking PDE5 to improve erectile dysfunction (ED). However, most PDE5 drugs revealed side effects including the loss of vision due to the PDE6 inhibition. Phenanthrene derivatives isolated from E. macrobulbon were previously reported as PDE5 inhibitors. Two phenanthrene derivatives (cpds 1-2) revealed better inhibition to PDE5 than PDE6 and cpd 1 is more selective to PDE5 than cpd 2. To elucidate why the phenanthrene derivatives could inhibit PDE5 and PDE6, their binding modes were investigated using molecular dynamics simulations and quantum chemical calculations, as compared to the PDE5 drugs. From the results, all four drugs and phenanthrene derivatives revealed similar π-π interactions to Phe820 in PDE5. Additional H-bond interaction to Gln817 in PDE5 resulted in better PDE5 inhibition of vardenafil and tadalafil. Moreover, cpds 1-2 were able to form the H-bond interaction with Asp764 in PDE5. In the case of the PDE6, the loss of π-π interaction to Phe776 and H-bond interaction to Gln773 indicated the important points for losing the PDE6 inhibition. In conclusion, to develop the new potent PDE5 inhibitors, not only the important interaction with PDE5 but also the interaction with PDE6 should be considered. In phenanthrene derivatives, the middle ring was significant to form π-π interactions to Phe820 in PDE5 and hydroxyl substituent was also the key part to form the H-bond interaction with Asp764 in PDE5. Principal component analysis (PCA) and free energy landscape (FEL) analysis indicated the stability of the system. The bioavailability, drug-likeness, and pharmacokinetics of phenanthrene derivatives were also predicted. These derivatives revealed good drug-likeness and GI absorption. The obtained results showed that phenanthrene derivatives could be interesting for the development of PDE5 inhibitors in the future.

Corrigendum: Severity of frailty using modified Thai Frailty Index, social factors, and prediction of mortality among community-dwelling older adults in a middle-income country.

[This corrects the article DOI: 10.3389/fmed.2022.1060990.].

Severity of frailty using modified Thai frailty index, social factors, and prediction of mortality among community-dwelling older adults in a middle-income country.

Background: Frailty has been increasingly recognized as a public health problem for aging populations with significant social impact, particularly in low- and middle-income countries. We aimed to develop a modified version of the Thai Frailty Index (TFI) and explore the association between different frailty statuses, socioeconomic factors, and mortality in community-dwelling older people from a middle-income country. Methods: The data from participants aged ≥60 years in the Fourth Thai National Health Examination Survey were used to construct the 30-item TFI. Cutoff points were created based on stratum-specific likelihood ratio. TFI ≤ 0.10 was categorized as fit, 0.10-0.25 as pre-frail, 0.25-0.45 as mildly frail, and >0.45 as severely frail. The association of frailty status with mortality was examined using Cox proportional hazard models. Findings: Among 8,195 older adults with a mean age of 69.2 years, 1,284 died during the 7-year follow-up. The prevalence of frailty was 16.6%. The adjusted hazard ratio (aHR) for mortality in pre-frail was 1.76 (95% CI = 1.50-2.07), mildly frail 2.79 (95% CI = 2.33-3.35), and severely frail 6.34 (95% CI = 4.60-8.73). Having a caretaker in the same household alleviated mortality risk for severely frail participants with an aHR of 2.93 (95% CI = 1.92-4.46) compared with an aHR of 6.89 (95% CI = 3.87-12.26) among those living without a caretaker. Interpretation: The severity of frailty classified by the modified TFI can predict long-term mortality risk for community-dwelling older adults. Identification of severely frail older people to provide appropriate care might alleviate mortality risk. Our findings can inform policymakers to appropriately allocate services in a resource-limited setting.

Binding interaction of protoberberine alkaloids against acetylcholinesterase (AChE) using molecular dynamics simulations and QM/MM calculations.

Acetylcholinesterase (AChE) plays a vital role in Alzheimer's disease (AD), which is one of the most common causes of dementia. Discovering new effective inhibitors against AChE activity is seen to be one of the effective approaches to reduce the suffering from AD. Protoberberine alkaloids isolated from natural resources have previously been reported as potent AChE inhibitors. In order to gain insights into how these alkaloids could inhibit AChE, berberine, palmatine, and cyclanoline were selected to investigate in terms of binding orientation and their key interactions with AChE using molecular docking and molecular dynamics simulations and quantum chemical calculations. The results revealed that the molecular dynamics structures of palmatine and berberine indicated that their equilibrated structures did not occupy the gorge but they slightly moved away from the catalytic site (CAS). For cyclanoline, the binding mode was quite different from those of donepezil and the other protoberberine alkaloids: it preferred to stay deeper in the CAS site. Interaction energies and residual interaction energies confirmed that the key interactions for palmatine and berberine were π-π interactions with Trp286 and Tyr341 and H-bond interactions with Tyr124. Cyclanoline formed π-π interactions with Trp86 and H-bonds to the amino acids in the CAS site. The results suggested the importance of aromaticity in the core structure and the flexibility of the core structure or the substituents in order to fit into the narrow gorge. The HOMO, LUMO, bioavailability, drug-likeness and pharmacokinetics were also predicted. The results obtained will be useful for further AD drug development.