Computational design of new protein kinase 2 inhibitors for the treatment of inflammatory diseases using QSAR, pharmacophore-structure-based virtual screening, and molecular dynamics.

Receptor-interacting protein kinase 2 (RIPK2) plays an essential role in autoimmune response and is suggested as a target for inflammatory diseases. A pharmacophore model was built from a dataset with ponatinib (template) and 18 RIPK2 inhibitors selected from BindingDB database. The pharmacophore model validation was performed by multiple linear regression (MLR). The statistical quality of the model was evaluated by the correlation coefficient (R), squared correlation coefficient (R2), explanatory variance (adjusted R2), standard error of estimate (SEE), and variance ratio (F). The best pharmacophore model has one aromatic group (LEU24 residue interaction) and two hydrogen bonding acceptor groups (MET98 and TYR97 residues interaction), having a score of 24.739 with 14 aligned inhibitors, which were used in virtual screening via ZincPharmer server and the ZINC database (selected in function of the RMSD value). We determined theoretical values of biological activity (logRA) by MLR, pharmacokinetic and toxicology properties, and made molecular docking studies comparing binding affinity (kcal/mol) results with the most active compound of the study (ponatinib) and WEHI-345. Nine compounds from the ZINC database show satisfactory results, yielding among those selected, the compound ZINC01540228, as the most promising RIPK2 inhibitor. After binding free energy calculations, the following molecular dynamics simulations showed that the receptor protein's backbone remained stable after the introduction of ligands.

Step by step male to female transsexual surgery.

INTRODUCTION: After the diagnosis of transsexualism is confirmed therapy commences with psychotherapeutic preparation for the conversion, and after conversion, long-term patient rehabilitation is maintained for at least two years. The indication for surgery is chronic discomfort caused by discord with the patient's natural gender, intense dislike of developing secondary sex characteristics and the onset of puberty. The surgical conversion of transsexuals is the main step in the complex care of these problematic patients (1). This surgery was first described by Benjamin H, using a flap of inverted penile skin (2) and is considered the gold standard since then. Male-to-female transsexual surgical techniques are well defined and give good cosmetic and functional results. Sex reassignment surgery promotes the improvement of psychological aspects and social relationships as shown in the World Health Organization Quality of Life Assessment applied in the patients submitted to this procedure (3). Techniques include the creation of a normal appearing female introitus, a vaginoplasty allowing sexual intercourse and the capability of clitoral orgasm (4). Various methods for neovaginoplasty have been described and can be classified into five categories, i.e. pedicled intestinal transplants, penile skin grafts, penile skin flaps, non-genital skin flaps and non-genital skin grafts (5). In our Hospital, we use penile and scrotal skin flaps. Until now, 174 procedures have been performed by our team using this technique with high rates of satisfaction (3). PATIENTS AND METHODS: We present a step-by-step male to female transsexual surgery. CONCLUSION: Surgical gender reassignment of male transsexuals resulted in replicas of female genitalia which enabled coitus with orgasm (1). With this video we show step by step that a surgery using penile skin flaps is able to be performed with good cosmetic results.

Exploration of the Acetylcholinesterase Inhibitory Activity of Some Alkaloids from Amaryllidaceae Family by Molecular Docking In Silico.

Alzheimer's disease (AD) is a progressive condition, where dementia symptoms gradually worsen. Biochemically the disease is characterized by the presence of neuritic plaques, neurofibrillary tangles, in addition to cholinergic dysfunction in the central nervous system. The role of the cholinergic neurotransmission in AD is the basis of the widely accepted cholinergic hypothesis. Some of the most relevant therapies for the treatment of the disease are based on the acetylcholinesterase (AChE) inhibitor activity; however, these therapies are not effective to stop the disease progression, but only can temporarily slow down the worsening of dementia symptoms, and improve quality of life of patients and their caregivers. In recent years, plant alkaloids extracted from Amaryllidaceae family have received great attention due to the well-known anti cholinergic activity. In this context, the purpose of this study was to apply the docking molecular in sílico analysis aiming to examine the recombinant human AChE enzyme (rhAChE) inhibitory activity displayed by different alkaloids from Amaryllidaceae family. Overall, the present results support the idea that alkaloids reported in this research are capable of interacting with rhAChE-binding sites.