Network-based drug repositioning of linagliptin as a potential agent for uterine fibroids targeting transforming growth factor-beta mediated fibrosis.

Uterine fibroid is the most common non-cancerous tumor with no satisfactory options for long-term pharmacological treatment. Fibroblast activation protein-α (FAP) is one of the critical enzymes that enhances the fibrosis in uterine fibroids. Through STITCH database mining, we found that dipeptidyl peptidase-4 inhibitors (DPP4i) have the potential to inhibit the activity of FAP. Both DPP4 and FAP belong to the dipeptidyl peptidase family and share a similar catalytic domain. Hence, ligands which have a binding affinity with DPP4 could also bind with FAP. Among the DPP4i, linagliptin exhibited the highest binding affinity (Dock score = -8.562 kcal/mol) with FAP. Our study uncovered that the differences in the S2 extensive-subsite residues between DPP4 and FAP could serve as a basis for designing selective inhibitors specifically targeting FAP. Furthermore, in a dynamic environment, linagliptin was able to destabilize the dimerization interface of FAP, resulting in potential inhibition of its biological activity. True to the in-silico results, linagliptin reduced the fibrotic process in estrogen and progesterone-induced fibrosis in rat uterus. Furthermore, linagliptin reduced the gene expression of transforming growth factor-ß (TGF-ß), a critical factor in collagen secretion and fibrotic process. Masson trichrome staining confirmed that the anti-fibrotic effects of linagliptin were due to its ability to reduce collagen deposition in rat uterus. Altogether, our research proposes that linagliptin has the potential to be repurposed for the treatment of uterine fibroids.

Syringaresinol as a novel androgen receptor antagonist against wild and mutant androgen receptors for the treatment of castration-resistant prostate cancer: molecular docking, in-vitro and molecular dynamics study.

Phytoestrogens are dietary estrogens having similar structure as of estrogen. Some of these phytoestrogens are androgen receptor (AR) antagonists and exhibit preventive role in the prostate cancer. However, in androgen-independent prostate cancer (AIPC) the ARs were mutated (T877A, W741L, F876L, etc.) and these mutant ARs convert the antagonist to agonist. Our aim in this study is to find phytoestrogens that could function as an antagonist with wild and mutant ARs. The phytoestrogens were analyzed for binding affinity with wild and mutant ARs in agonist and antagonist conformations. The point mutations were carried out using Chimera. The antagonist AR conformation was modeled using Modeller. We hypothesize that the compounds having binding affinity with agonist AR conformation could not function as a full or pure antagonist. Most of the phytoestrogens have binding affinity with agonist AR conformation contradicting previous results. For example, genistein which is a widely studied isoflavone has known AR antagonist property. However, in our study, it had good binding affinity with agonist AR conformation. Hence, to confirm our hypothesis, we tested genistein in LNCaP (T877A mutant AR) cells by qPCR studies. The genistein functioned as an antagonist only in the presence of an androgen indicting a partial agonist type of activity. The in-vitro results supported our docking hypothesis. We applied this principle and found syringaresinol could function as an antagonist with wild and mutated ARs. Further, we carried out molecular dynamics for the hit molecule to confirm its antagonist binding mode with mutant AR.Communicated by Ramaswamy H. Sarma.

An in-silico approach: identification of PPAR-γ agonists from seaweeds for the management of Alzheimer's Disease.

Alzheimer's Disease is a complex progressive neurodegenerative disorder characterized by neurofibrillary tangles and senile plaques in various parts of the brain particularly cerebral cortex affecting memory and cognition. Nuclear receptors such as Peroxisome proliferator-activated receptor γ [PPAR-γ] is reported to have a role in lipid and glucose homeostasis in the brain, reduces the synthesis of Aß (beta-amyloid plaques) and also regulates mitochondrial biogenesis and inhibit the neuro-inflammation, which contributes for the improvement in the cognitive function in AD. Hence PPAR-γ is one of the newer targets for the researchers to understand the pathology of AD and to evolve the novel strategy to retard/reverse the progression of AD. PPAR-γ agonists such as Rosiglitazone and Pioglitazone have shown promising results in AD by decreasing neuro-inflammation and restoring glucose dysmetabolism leading to a reduction in neuronal deterioration. These agonists possess poor blood-brain permeability and are poor candidates for clinical use in AD. Therefore, search, design, and development for new PPAR- γ agonists with improved BBB penetration ability are imperative. The present work deals with the use of computational tools and techniques such as molecular docking, molecular dynamics to discover PPAR-γ agonists from the unexplored Seaweed Metabolite Database and predicts it's toxicological and physiochemical profile, thereby saving time and resources. Out of 1,110 seaweed compounds, the hit molecule BS052 displayed a strong binding affinity towards PPAR-γ, which possessed better lipid solubility indicating the potential to be considered as a PPAR-γ agonist, which may be useful in the management of AD.Communicated by Ramaswamy H. Sarma.