An amalgamated molecular dynamic and Gaussian based 3D-QSAR study for the design of 2,4-thiazolidinediones as potential PTP1B inhibitors.

Overexpression of protein tyrosine phosphatase 1B (PTP1B) is the major cause of various diseases such as diabetes, obesity, and cancer. PTP1B has been identified as a negative regulator of the insulin signaling cascade, thereby causing diabetes. Numerous anti-diabetic medications based on thiazolidinedione have been successfully developed; however, 2,4-thiazolidinedione (2,4-TZD) scaffolds have been reported as potential PTP1B inhibitors for the manifestation of type 2 diabetes mellitus involving insulin resistance. In the present study, we have employed amalgamated approach involving MD-simulation studies (100 ns) as well as Gaussian field-based 3D-QSAR to develop a pharmacophoric model of 2,4-TZD as potent PTP1B inhibitors. MD simulation studies of the most potent compound in the PTP1B (PDB Id: 2QBS) binding pocket revealed that compound 43 was stable in the binding pocket and demonstrated excellent binding efficacy within the active site pocket. MM/GBSA results revealed that compound 43, bearing C-5 arylidine substitution, strongly bound to the target as compared to rosiglitazone with ΔGMM/GBSA difference of -11.13 kcal/mol. PCA, Rg, RMSF, RMSD, and SASA were analyzed from the complex's trajectories to anticipate the simulation outcome. We have suggested a series of 2,4-TZD as possible PTP1B inhibitors based on the results of MD simulation and 3D-QSAR studies.

Medicinal Aspects of PTP 1B Inhibitors as Anti-Breast Cancer Agents: An Overview.

Protein tyrosine phosphatase 1B (PTP1B) has gained interest as a therapeutic target for type 2 diabetes and obesity. Besides metabolic signalling, PTP1B is a positive regulator of signalling pathways linked to ErbB2-induced breast tumorigenesis. Substantial evidence proves that its overexpression is involved in breast cancer, which suggests that selective PTP1B inhibition might be effective in breast cancer treatment. Therefore, huge research is being carried out on PTP1B inhibitors and their activity against breast cancer development. To date, only two PTP1B inhibitors, viz. ertiprotafib and trodusquemine, have entered clinical trials. The discovery of selective inhibitors of PTP1B could open a new avenue in breast cancer treatment. In this review, we provide an extensive overview on the involvement of PTP1B in breast cancer, its pathophysiology, with special attention on the discovery and development of various natural as well as synthetic PTP1B inhibitors. This study will provide significant information to the researchers developing PTP1B inhibitors for breast cancer treatment.

Microsponges as Drug Delivery System: Past, Present, and Future Perspectives.

Microsponges are polymeric delivery devices composed of porous microspheres that range in size from 5 to 300 micrometers. These have been explored for biomedical applications such as targeted drug delivery, transdermal drug delivery, anticancer drug delivery, and bone substitutes. The purpose of this study is to conduct a comprehensive analysis of recent developments and prospects for a microsponge-based drug delivery system. The current study analyzes how the Microsponge Delivery System (MDS) is made, how it works, and how it can be used for a wide range of therapeutic purposes. The therapeutic potential and patent information of microsponge-based formulations were systematically analyzed. The authors summarize various effective techniques for developing microsponges, such as liquid-liquid suspension polymerization, quasi-emulsion solvent diffusion method, water-in-oil-in-water (w/o/w) emulsion solvent diffusion, oil-in-oil emulsion solvent diffusion, lyophilization method, porogen addition method, vibrating orifice aerosol generator method, electrohydrodynamic atomization method, and ultrasound-assisted microsponge. Microsponge may reduce the side effects and increase drug stability by positively altering drug release. Drugs that are both hydrophilic and hydrophobic can be loaded into a microsponge and delivered to a specific target. The microsponge delivery technology offers numerous advantages over conventional delivery systems. Microsponges, which are spherical sponge-like nanoparticles with porous surfaces, have the potential to increase the stability of medications. They also efficiently decrease the undesirable effects and alter drug release.

Multifaceted 3D-QSAR analysis for the identification of pharmacophoric features of biphenyl analogues as aromatase inhibitors.

Aromatase, a cytochrome P450 enzyme, is responsible for the conversion of androgens to estrogens, which fuel the multiplication of cancerous cells. Inhibition of estrogen biosynthesis by aromatase inhibitors (AIs) is one of the highly advanced therapeutic approach available for the treatment of estrogen-positive breast cancer. Biphenyl moiety aids lipophilicity to the conjugated scaffold and enhances the accessibility of the ligand to the target. The present study is focused on the investigation of, the mode of binding of biphenyl with aromatase, prediction of ligand-target binding affinities, and pharmacophoric features essential for favorable for aromatase inhibition. A multifaceted 3D-QSAR (SOMFA, Field and Gaussian) along with molecular docking, molecular dynamic simulations and pharmacophore mapping were performed on a series of biphenyl bearing molecules (1-33) with a wide range of aromatase inhibitory activity (0.15-920 nM). Among the generated 3D-QSAR models, the Force field-based 3D-QSAR model (R2 = 0.9151) was best as compared to SOMFA and Gaussian Field (R2=0.7706, 0.9074, respectively). However, all the generated 3D-QSAR models were statistically fit, robust enough, and reliable to explain the variation in biological activity in relation to pharmacophoric features of dataset molecules. A four-point pharmacophoric features with three acceptor sites (A), one aromatic ring (R) features, AAAR_1, were obtained with the site and survival score values 0.890 and 4.613, respectively. The generated 3D-QSAR plots in the study insight into the structure-activity relationship of dataset molecules, which may help in the designing of potent biphenyl derivatives as newer inhibitors of aromatase.Communicated by Ramaswamy H. Sarma.

Experimental Animal Models: Tools to Investigate Antidiabetic Activity.

About 2.8% of the global population are being suffered from Diabetes mellitus. Diabetes mellitus is a group of metabolic disorders that is characterized by an absolute lack of insulin and resulting in hyperglycemia. To overcome the challenges, many antidiabetic drugs are being used, and research is being carried out in search of more effective anti-diabetic drugs. To study the effectiveness of antidiabetic drugs, many diabetic models, chemicals, and diabetogenic hormones were used at the research level. In this review, we summarised various animal models used, chemicals that induce diabetes, their properties, and the mechanism of action of these models. Further, diabetes mellitus is generally induced in laboratory animals by several methods that include: chemical, surgical and genetic manipulations. To better understand both the pathogenesis and potential therapeutic agents, appropriate animal models of type 1 & type 2 diabetes mellitus are needed. However, for an animal model to have relevance to the study of diabetes, either the characteristics of the animal model should mirror the pathophysiology and natural history of diabetes or the model should develop complications of diabetes with an etiology similar to that of the human condition. There appears to be no single animal model that encompasses all of these characteristics, but there are many that provide very similar characteristics in one or more aspects of diabetes in humans. The use of the appropriate animal model based on these similarities can provide much-needed data on pathophysiological mechanisms operative in human diabetes.

Flavonoids as promising anticancer agents: an in silico investigation of ADMET, binding affinity by molecular docking and molecular dynamics simulations.

Cancer is one of the most concerning diseases to humankind. Various treatment strategies are being employed for its treatment, out of which use of natural products is an essential one. Flavonoids have proven to be promising anticancer targets since decades. Also, tubulin is a significant biological target for the development of anticancer agents due to its crucial role in mitosis and abundance throughout the body. In the current study, in silico ADMET parameters of 104 flavonoids were examined, followed by molecular docking with the colchicine binding site of Tubulin protein (PDB; Id 4O2B). The best conformation from each flavonoid subcategory with the best docking score (MolDock score) was further subjected to 100 ns of molecular dynamics to investigate the protein-ligand complex's stability. Different parameters such as RMSD, RMSF, rGy and SASA were calculated for the six flavonoids using molecular dynamic studies. The top most compound from all the six subcategories of flavonoids elicited best behavior in the colchicine binding site of Tubulin protein. This in silico study employing molecular docking and molecular dynamics simulation provides strong evidence for flavonoids to be excellent anti-tubulin agents for the treatment of cancer.Communicated by Ramaswamy H. Sarma.

Recent Advancement of Polymersomes as Drug Delivery Carrier.

BACKGROUND: Biomedical applications of polymersomes have been explored, including drug and gene delivery, insulin delivery, hemoglobin delivery, the delivery of anticancer agents, and various diagnostic purposes. OBJECTIVES: Polymersomes, which are self-assembled amphiphilic block copolymers, have received a lot of attention in drug delivery approaches. This review represents the methods of preparation of polymersomes, including thin-film rehydration, electroformation, double emulsion, gel-assisted rehydration, PAPYRUS method, and solvent injection methods, including various therapeutic applications of polymersomes. METHODS: Data was searched from PubMed, Google Scholar, and Science Direct through searching of the following keywords: Polymersomes, methods of preparation, amphiphilic block copolymers, anticancer drug delivery. RESULTS: Polymersomes provide both hydrophilic and hydrophobic drug delivery to a targeted site, increasing the formulation's stability and reducing the cytotoxic side effects of drugs. CONCLUSION: Polymersomes have the potential to be used in a variety of biological applications, including drug and gene delivery, insulin delivery, hemoglobin delivery, delivery of anticancer agents, as well as in various diagnostic purposes. Recently, polymersomes have been used more frequently because of their stability, reducing the encapsulated drug's leakage, site-specific drug delivery, and increasing the bioavailability of the drugs and different diagnostic purposes. The liposomes encapsulate only hydrophilic drugs, but polymersomes encapsulate both hydrophilic and hydrophobic drugs in their cores.

Dual Aromatase-Sulphatase Inhibitors (DASIs) for the Treatment of Hormone Dependent Breast Cancer.

Breast cancer is the most frequently diagnosed cancer in women and the second most common form of cancer, causing death after lung cancer, all across the globe at an alarming rate. The level of estrogens in breast cancer tissues of postmenopausal women is 10-40 folds higher than the non-carcinogenic breast tissues. As a result of this greater level of estrogen, breast tissue becomes more prone to develop breast cancer; mainly, estradiol plays a significant role in the initiation and development of hormone-dependent breast cancer. Androstenedione, Adrenal dehydroepiandrosterone sulfate, and estrone-sulfate also play an important role as precursors for estrogen biosynthesis. Estrogen deprivation exhibits an attractive phenomenon in the advancement of ideal therapeutics for the treatment of breast cancer. Inhibition of aromatase and sulphatase emerged as an attractive therapy for the treatment of hormone-dependent breast cancer via deprivation of estrogen by different pathways. The cocktail of aromatase and sulphatase inhibitors known as Dual Aromatase-sulphatase Inhibitors (DASIs) emerged as an attractive approach for effective estrogen deprivation. The present review article focused on the journey of dual aromatase-sulphatase inhibitors from the beginning to date (2020). Keeping in view the key observations, this review may be helpful for medicinal chemists to design and develop new and efficient dual aromatase-sulphatase inhibitors for the possible treatment of hormone- related breast cancer.

A Comprehension into Target Binding and Spatial Fingerprints of Noscapinoid Analogues as Inhibitors of Tubulin.

BACKGROUND: Owing to its potential to interfere in microtubule dynamics in the mitotic phase of cell cycle and selectively induce apoptosis in cancer cells without affecting normal cells, noscapine and its synthetic analogues have been investigated by other research groups in different cell lines for their capability to be used as anti-cancer agents. OBJECTIVE: The present study is focused on the investigation of the mode of binding of noscapinoids with tubulin, prediction of target binding affinities and mapping of their spatial fingerprints (shape and electrostatic). METHODS: Molecular docking assisted alignment based 3D-QSAR was used on a dataset (43 molecules) having an inhibitory activity (IC50 = 1.2-250 µM) against human lymphoblast (CEM) cell line. RESULTS AND CONCLUSION: Key amino acid residues of target tubulin were mapped for the binding of most potent noscapine analogue (Compound 11) and were compared with noscapine. Spatial fingerprints of noscapinoids for favorable tubulin inhibitory activity were generated and are proposed herewith for further pharmacophoric amendments of noscapine analogues to design and develop novel potent noscapine based anti-cancer agents that may enter into drug development pipeline.

Mannose Conjugated Starch Nanoparticles for Preferential Targeting of Liver Cancer.

AIM: To design D-Mannose conjugated 5-Fluorouracil (5-FU) loaded Jackfruit Seed Starch Nanoparticles (JFSSNPs) for site-specific delivery. BACKGROUND: Liver cancer is the third leading cause of death in the world and the fifth most often diagnosed cancer. It is a major global threat to public health. Treatment of liver cancer with conventional method bears several side effects, thus to undertake these side effects as a formulation challenge, it is necessary to develop novel target-specific drug delivery system for the effective and better localization of drug into the proximity of target with restricting the movement of the drug in normal tissues. OBJECTIVE: To optimize and characterize the developed D-Mannose conjugated 5-Fluorouracil (5- FU) loaded Jackfruit Seed Starch Nanoparticles (JFSSNPs) for effective treatment of liver cancer. MATERIALS AND METHODS: 5-FU loaded JFSSNPs were prepared and optimized formulations having higher encapsulation efficiency were conjugated with D-Mannose. These formulations were characterized for size, morphology, zeta potential, X-Ray Diffraction, and Differential Scanning Calorimetry. The potential of NPs was studied using in vitro cytotoxicity assay, in vivo kinetic studies, and bio-distribution studies. RESULT AND DISCUSSION: 5-Fluorouracil loaded NPs had a particle size between 336 to 802 nm with drug entrapment efficiency between 64.2 to 82.3%. In XRD analysis, 5-FU peak was diminished in the diffractogram, which could be attributed to the successful incorporation of the drug in amorphous form. DSC study suggests there was no physical interaction between 5-FU and Polymer. NPs showed sustained in vitro 5-FU release up to 2 hours. In vivo, mannose conjugated NPs prolonged the plasma level of 5-FU and assisted in the selective accumulation of 5-FU in the liver (vs. other organs spleen, kidney, lungs, and heart) compared to unconjugated one and plain drug. CONCLUSION: In vivo, bio-distribution, and plasma profile studies resulted in a significantly higher concentration of 5-Fluorouracil liver, suggesting that these carriers are efficient, viable, and targeted carrier of 5-FU treatment of liver cancer.

Effective insulin delivery using starch nanoparticles as a potential trans-nasal mucoadhesive carrier.

Mucoadhesive nanoparticles (NPs) could be an exciting prospect for trans-nasal insulin delivery as they have higher surface area to cover highly vascularised nasal absorptive area providing a greater concentration gradient; hence the present study makes an attempt in this regard. Starch NPs were prepared by different crosslinkers using various methodologies and were loaded with insulin. Emulsion crosslinked particles were smaller in size compared to gel method (351 vs 997 nm), and size is further reduced when epichlorohydrin is used as crosslinking agent compared to POCl3 (194 vs 810 nm). NPs of epichlorohydrin emulsion were further optimized with variable crosslinking to evaluate the effect of degree of crosslinking on in vivo performance. In vitro, a size dependent first order diffusion controlled insulin release with an initial burst effect was found, which is higher with NPs of small size and least crosslinking. Formulation of EE-NPs with Na glycocholate showed a superior hypoglycemic action compared to other NPs formulations containing the former and lysophosphatidylcholine as permeation enhancers. The hypoglycemic effects were more pronounced with medium crosslinked NPs (EE-L2-NPs), which showed a nadir of 70% reduction of plasma glucose and significant effects until 6h. The peak plasma insulin level (Cmax) of medium crosslinked EE-L2-NPs (258 muIU/ml at 1h) vindicates the pharmacodynamic effect, which was found to be superior compared to all other formulations. The release rate and higher associated surface area might work in tandem, and could be greatly amplified when combined with permeation enhancers to make starch NPs an efficient trans-nasal mucoadhesive carrier of insulin.