Designing dual inhibitors for the treatment of Alzheimer’s disease as well as Type 2 diabetes mellitus via pharmacoinformatics approach: A step towards better medication for diabetes-associated neurological disorder

Purpose: To design dual inhibitors against Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) via pharmacoinformatics approach.Methods: Dual Drug Candidates (DDC) were designed and explored for their molecular interaction with several AD and T2DM targets. Pterostilbene, a natural anti-T2DM compound was coupled with different cholinesterase inhibitors to design DDC. Orisis Datawarrior online property calculator  tools, Autock 4.2 and Hex 5.1 were used to investigate the potency of all DDC relative to positive controls.Results: The study found that DDC2 (pterostilbene - methylene linker -octa hydro amino phenothiazine), DDC3 (pterostilbene - ethylene linker - N-phthalimide) and DDC5 (pterostilbene - carbonyl linker - 2-methyl-4-aminoquinoline) were the most promising out of all the DDCs. DDC2 showed strong molecular interaction with most of the AD and T2DM targets, including acetylcholinesterase, butrylcholinesterase, β-secretase, receptor for advanced glycation end products and ATP sensitive potassium channel, dipeptidyl peptidase IV and sodium glucose transport protien 2. The findings also revealed the amyloid anti-aggregation potential of DDC.Conclusion: The results show that DDC3 and DDC5 significantly interfer with the primary nucleation process of β amyloid. Thus, DDC2, DDC3 and DDC5 have strong anti-T2DM and anti-AD potential. Keywords: Type 2 Diabetes Mellitus, Alzheimer’s disease, Dual drug candidate, Amyloid-beta, Pterostilben

Short-term treatment with tolfenamic acid improves cognitive functions in Alzheimer\u27s disease mice

Tolfenamic acid lowers the levels of the amyloid precursor protein (APP) and amyloid beta (Aβ) when administered to C57BL/6 mice by lowering their transcriptional regulator specificity protein 1 (SP1). To determine whether changes upstream in the amyloidogenic pathway that forms Aβ plaques would improve cognitive outcomes, we administered tolfenamic acid for 34 days to hemizygous R1.40 transgenic mice. After the characterization of cognitive deficits in these mice, assessment of spatial learning and memory functions revealed that treatment with tolfenamic acid attenuated long-term memory and working memory deficits, determined using Morris water maze and the Y-maze. These improvements occurred within a shorter period of exposure than that seen with clinically approved drugs. Cognitive enhancement was accompanied by reduction in the levels of the SP1 protein (but not messenger RNA [mRNA]), followed by lowering both the mRNA and the protein levels of APP and subsequent Aβ levels. These findings provide evidence that tolfenamic acid can disrupt the pathologic processes associated with Alzheimer\u27s disease (AD) and are relevant to its scheduled biomarker study in AD patients

Infantile exposure to lead and late-age cognitive decline: Relevance to AD

Background: Early-life lead (Pb) exposure induces overexpression of the amyloid beta precursor protein and its amyloid beta product in older rats and primates. We exposed rodents to Pb during different life span periods and examined cognitive function in old age and its impact on biomarkers associated with Alzheimer\u27s disease (AD). Methods: Morris, Y, and the elevated plus mazes were used. Western blot, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay were used to study the levels of AD biomarkers. Results: Cognitive impairment was observed in mice exposed as infants but not as adults. Overexpression of AD-related genes (amyloid beta precursor protein and β-site amyloid precursor protein cleaving enzyme 1) and their products, as well as their transcriptional regulator—specificity protein 1 (Sp1)—occurred only in older mice with developmental exposure to Pb. Conclusions: A window of vulnerability to Pb neurotoxicity exists in the developing brain that can influence AD pathogenesis and cognitive decline in old age

Molecular docking and dynamic simulation study to explore quercetin as a multi-potent candidate against gliomas

Purpose: To search for novel gliomas targets and their inhibitors using a molecular docking approach. Methods: Quercetin multi-targeting potential was investigated against some of the emerging gliomas targets such as epidermal growth factor receptor (EGFR), ephrin type-A receptor 2 (EphA2), nicotinamide phosphoribosyltransferase (NMRPTase) and plasminogen activator inhibitor-1 (PAI-1). Crucial biochemical interaction of quercetin with these targets were analyzed using molecular docking study. Results: Quercetin interacted strongly via hydrogen bonding with important active sites consisting of amino acid residues of EphA2 and PAI-1, and showed binding energy of -7.44 and -7.38 kcal/mol, respectively. Some crucial active site amino acids involved in the interaction of known EphA2 and PAI-1 inhibitors (Alw-II-41-27 and ACT001) were common in quercetin interactions as well, and both inhibitors as well as quercetin did not violate Lipinski rules. Importantly, the quercetin-EphA2 and quercetin-PAI-1 complexes were stable as minimal fluctuations within the permissible limit were observed during a 20 ns trajectory performed on desmond simulation platform. Conclusion: Despite the fact that quercetin has been studied extensively against various cancer pathways, its transformation from a long-time bench candidate into bedside medications still needs further exploration. Nevertheless, the present predictive biochemical interaction analysis against emerging glioma targets might pave way for the design of novel therapeutic agents based on quercetin scaffolds

Current Status of Brain Tumor in the Kingdom of Saudi Arabia and Application of Nanobiotechnology for Its Treatment: A Comprehensive Review

Objective: Brain tumors are the most challenging of all tumors and accounts for about 3% of all cancer allied deaths. The aim of the present review is to examine the brain tumor prevalence and treatment modalities available in the Kingdom of Saudi Arabia. It also provides a comprehensive analysis of the application of various nanotechnology-based products for brain cancer treatments along with their prospective future advancements. Methods: A literature review was performed to identify and summarize the current status of brain cancer in Saudi Arabia and the scope of nanobiotechnology in its treatment. Results: Depending upon the study population data analysis, gliomas, astrocytoma, meningioma, and metastatic cancer have a higher incidence rate in Saudi Arabia than in other countries, and are mostly treated in accordance with conventional treatment modalities for brain cancer. Due to the poor prognosis of cancer, it has an average survival rate of 2 years. Conventional therapy includes surgery, radiotherapy, chemotherapy, and a combination thereof, but these do not control the disease’s recurrence. Among the various nanomaterials discussed, liposomes and polymeric nanoformulations have demonstrated encouraging outcomes for facilitated brain cancer treatment. Conclusions: Nanomaterials possess the capacity to overcome the shortcomings of conventional therapies. Polymer-based nanomaterials have shown encouraging outcomes against brain cancer when amalgamated with other nano-based therapies. Nonetheless, nanomaterials could be devised that possess minimal toxicity towards normal cells or that specifically target tumor cells. In addition, rigorous clinical investigations are warranted to prepare them as an efficient and safe modality for brain cancer therapy