Nasimul Hoda

Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease.

Neurodegenerative diseases are among the most challenging diseases with poorly known mechanism of cause and paucity of complete cure. Out of all the neurodegenerative diseases, Alzheimers disease is the most devastating and loosening of thinking and judging ability disease that occurs in the old age people. Many hypotheses came forth in order to explain its causes. In this review, we have enlightened Glycogen Synthase Kinase-3 which has been considered as a concrete cause for Alzheimers disease. Plaques and Tangles (abnormal structures) are the basic suspects in damaging and killing of nerve cells wherein Glycogen Synthase Kinase-3 has a key role in the formation of these fatal accumulations. Various Glycogen Synthase Kinase-3 inhibitors have been reported to reduce the amount of amyloid-beta as well as the tau hyperphosphorylation in both neuronal and nonneuronal cells. Additionally, Glycogen Synthase Kinase-3 inhibitors have been reported to enhance the adult hippocampal neurogenesis in vivo as well as in vitro. Keeping the chemotype of the reported Glycogen Synthase Kinase-3 inhibitors in consideration, they may be grouped into natural inhibitors, inorganic metal ions, organo-synthetic, and peptide like inhibitors. On the basis of their mode of binding to the constituent enzyme, they may also be grouped as ATP, nonATP, and allosteric binding sites competitive inhibitors. ATP competitive inhibitors were known earlier inhibitors but they lack efficient selectivity. This led to find the new ways for the enzyme inhibition.

Curcumin specifically binds to the human calcium–calmodulin-dependent protein kinase IV: fluorescence and molecular dynamics simulation studies

Calcium–calmodulin-dependent protein kinase IV (CAMK4) plays significant role in the regulation of calcium-dependent gene expression, and thus, it is involved in varieties of cellular functions such as cell signaling and neuronal survival. On the other hand, curcumin, a naturally occurring yellow bioactive component of turmeric possesses wide spectrum of biological actions, and it is widely used to treat atherosclerosis, diabetes, cancer, and inflammation. It also acts as an antioxidant. Here, we studied the interaction of curcumin with human CAMK4 at pH 7.4 using molecular docking, molecular dynamics (MD) simulations, fluorescence binding, and surface plasmon resonance (SPR) methods. We performed MD simulations for both neutral and anionic forms of CAMK4-curcumin complexes for a reasonably long time (150 ns) to see the overall stability of the protein–ligand complex. Molecular docking studies revealed that the curcumin binds in the large hydrophobic cavity of kinase domain of CAMK4 through several hydrophobic and hydrogen-bonded interactions. Additionally, MD simulations studies contributed in understanding the stability of protein–ligand complex system in aqueous solution and conformational changes in the CAMK4 upon binding of curcumin. A significant increase in the fluorescence intensity at 495 nm was observed (λexc = 425 nm), suggesting a strong interaction of curcumin to the CAMK4. A high binding affinity (KD = 3.7 × 10−8 ± .03 M) of curcumin for the CAMK4 was measured by SPR further indicating curcumin as a potential ligand for the CAMK4. This study will provide insights into designing a new inspired curcumin derivatives as therapeutic agents against many life-threatening diseases.

Coumarin: A Privileged Scaffold for the Design and Development of Antineurodegenerative Agents

Drug development for neurodegenerative diseases (NDs) is foremost task for the medicinal chemists in the 21st century. Coumarins are exemplary of an assorted and aptitudinally useful set of drugs. Coumarins play a momentous role in several pharmacological and medicinal aspects. Its analogues are anticipated to play a significant role in the development of new therapeutic leads for NDs. Their promising applications in the field of ND medication are exemplified by clinical candidates such as nodakenin that have been potent for demoting memory impairment. Apart from ND, clinically used anticoagulant warfarin, anticoagulant dicoumarol, and antibiotic coumermycin, novobiocin and chartesium grab the interest of researchers in coumarins. It would be worthwhile to look at the different biological processes that could cause neurodegeneration, thereby establishing a link with distinct coumarin derivatives to serve the purpose of medication. This review undertakes estimation of the wide spectrum of studies focusing coumarin to the domain of drug research for ND. Herein, we search for multitarget coumarin‐based inhibitors and their scope for NDs. Future challenges in coumarin‐based drug development have been discussed, and emphases have been laid on the future perspectives of coumarins as possible drugs in the future for the treatment of NDs.

Structure guided design of potential inhibitors of human calcium-calmodulin dependent protein kinase IV containing pyrimidine scaffold.

Calmodulin dependent protein kinase IV (CAMKIV) belongs to the serine/threonine protein kinase family and considered as an encouraging target for the development of novel anticancer agents. The interaction and binding behavior of three designed inhibitors of human CAMKIV, containing pyrimidine scaffold, was monitored by in vitro fluorescence titration and molecular docking calculations under physiological condition. In silico docking studies were performed to screen several compounds containing pyrimidine scaffold against CAMKIV. Molecular docking calculation predicted the binding of these ligands in active-site cavity of the CAMKIV structure correlating such interactions with a probable inhibition mechanism. Finally, three active pyrimidine substituted compounds (molecules 1-3) have been successfully synthesized and characterized by (1)H and (13)C NMR. Molecule 3 is showing very high binding-affinity for the CAMKIV, with a binding constant of 2.2×10(8), M(-1) (±0.20). All three compounds are nontoxic to HEK293 cells up to 50 μM. The cell proliferation inhibition study showed that the molecule 3 has lowest IC50 value (46±1.08 μM). The theoretical and experimental observations are significantly correlated. This study reveals some important observations to generate an improved pyrimidine based compound that holds promise as a therapeutic agent for the treatment of cancer and neurodegenerative diseases.

Design, synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin-dependent protein kinase IV.

Calcium/calmodulin‐dependent protein kinase IV (CAMKIV) is a multifunctional Ser/Thr kinase, associated with cerebral hypoxia, cancer, and neurodegenerative diseases. Here, we report design, synthesis, and biological evaluation of seven pyrimidine‐substituted novel inhibitors of CAMKIV. We successfully synthesized and extensively characterized (ESI‐MS, 1H NMR, and 13C NMR studies) seven compounds that are showing appreciable binding affinity to the CAMKIV. Molecular docking and fluorescence binding studies revealed that compound 1 is showing very high binding free energy (ΔG = −11.52 kcal/mol) and binding affinity (K = 9.2 × 1010 m−1) to the CAMKIV. We further performed MTT assay to check the cytotoxicity and anticancer activity of these compounds. An appreciable IC50 (39 μm) value of compound 1 was observed on human hepatoma cell line and nontoxic till the 400 μm on human embryonic kidney cells. To ensure anticancer activity of all these compounds, we further performed propidium iodide assay to evaluate cell viability and DNA content during the cell cycle. We found that compound 1 is again showing a better anticancer activity on both human hepatoma and human embryonic kidney cell lines.

Development of cyanopyridine-triazine hybrids as lead multitarget anti-Alzheimer agents.

A series of new cyanopyridine-triazine hybrids were designed, synthesized and screened as multitargeted anti-Alzheimers agents. These molecules were designed while using computational techniques and were synthesized via a feasible concurrent synthetic route. Inhibition potencies of synthetic compounds 4a-4h against cholinesterases, Aβ1-42 disaggregation, oxidative stress, cytotoxicity, and neuroprotection against Aβ1-42-induced toxicity of the synthesized compounds were evaluated. Compounds 4d and 4h showed promising inhibitory activity on acetylcholinesterase (AChE) with IC50 values 0.059 and 0.080μM, respectively, along with good inhibition selectivity against AChE over butyrylcholinesterase (BuChE). Molecular modelling studies revealed that these compounds interacted simultaneously with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The mixed type inhibition of compound 4d further confirmed their dual binding nature in kinetic studies. Furthermore, the results from neuroprotection studies of most potent compounds 4d and 4h indicate that these derivatives can reduce neuronal death induced by H2O2-mediated oxidative stress and Aβ1-42 induced cytotoxicity. In addition, in silico analysis of absorption, distribution, metabolism and excretion (ADME) profile of best compounds 4d and 4h revealed that they have drug like properties. Overall, these cyanopyridine-triazine hybrids can be considered as a candidate with potential impact for further pharmacological development in Alzheimers therapy.

Dihydroorotate dehydrogenase: A drug target for the development of antimalarials

Malaria is a critical human disease with extensive exploration yet unestablished due to occurrence of frequent drug resistance. This aspect of malaria pharmacology calls for the introduction of new antimalarial. The drugs reported till date targeted different stages of the parasites in order to stop their growth and proliferation. Beside this, various drugs that could inhibit the imperative enzymes of the parasite have also been reported. Amid them, dihydroorotate dehydrogenase (DHODH) has a key worth. DHODH is involved in the de novo pyrimidine biosynthesis of the malarial parasite which acts as a primary source of energy for its survival. Since life of the parasite utterly depends on pyrimidine biosynthesis, so it can be used as an apt drug target for malaria eradication. In addition to this, DHODH is also present in human and their active sites have significant structural dissimilarities, so the development of selective inhibitors may prove to be a milestone in search of new antimalarials. Inhibitors of human DHODH have been used to treat autoimmune diseases such as, rheumatoid arthritis or multiple sclerosis and have been investigated in the treatment of cancer, viral diseases, as well as in plant pathology. Here, we have reviewed the important role of DHODH as a viable drug target against malaria, its importance for the survival of the parasite, and DHODH inhibitors reported so far. The rate of success of the reported DHODH inhibitors and further required improvements have also been accounted.

Selective inhibitors of phosphodiesterases: therapeutic promise for neurodegenerative disorders

Neurodegenerative disease appears as a result of genomic lesions which lead to alterations at multiple levels like genomic product and biological pathways. It involves destruction of existing neuroprotective mechanisms inside body which initiates the cellular changes involved in processing of these insidious disorders. Phosphodiesterases that are crucial for degradation of cAMP and cGMP have been puissant in memory retrieval. Overwhelming therapeutic credential of PDE5 inhibitors have triggered interests in PDE inhibitors. Almost every PDE member has marked its presence in the CNS devising them as enticing sources of novel protein targets for curing ND. This review describes a selection of recent findings and advancements with regards to PDE genes that are crucial for exploring pharmacological routes to ND.

GSK3 Inhibitors in the Therapeutic Development of Diabetes, Cancer and Neurodegeneration: Past, Present and Future.

GSK3 has gained a considerable attention of researchers in the late 1970s as an inevitable drug target to treat diabetes. Furthermore, it was found to have a key role in the development of diseases like cancer and neurodegeneration (ND). A broad spectrum of GSK3 inhibitors have been discovered from time to time in order to curb these diseases. Inhibition of GSK3 by insulin boosts the dephosphorylation of glycogen synthase, hence its activation to convert UDP glucose into glycogen. Lack of insulin and insulin-resistance is supposed to be the cause of type 2 diabetes (Diabetes mellitus). Additionally, GSK3 stabilizes the components of beta-catenin complex, hence promotes oncogenesis. Phosphorylation of GSK3 by Akt and some other kinases also favours the carcinogenesis. However, in some cases GSK3 has tumor supressing character. GSK3 has been found to have a prominent role in the formation of amyloid plaques and neurofibrillary tangles (abnormal protein accumulations) which are the main suspects of Alzheimers disease (AD). GSK3 inhibitors have been reported to have amyloidbeta disaggregation property and have been found to promote the adult hippocampal neurogenesis in vivo as well as in vitro. This manuscript thoroughly reviews the involvement of GSK3 in diabetes, cancer and ND. Furthermore, development of GSK3 inhibitors as antidiabetes, anticancer and antineurodegenerative agents focusing mainly on lead optimization has been discussed.

Okra gum–alginate composites for controlled releasing drug delivery

Abstract Since past few years, various ionotropically cross-linked alginate-based composites have been researched as controlled sustained drug delivery dosage forms for oral administration. Almost all these ionotropically cross-linked alginate-based composites have shown good drug encapsulations and excellent control of sustained drug release. Particular attention has recently been placed on development of ionotropically cross-linked alginate–plant polysaccharides composites for controlling drug release. Okra gum (OkG, extracted from the immature and tender fruits of Hibiscus esculentus plants, family: Malvaceae) is one of the plant-derived polysaccharides, which has been recently exploited as composite material to develop composite beads made of OkG-ionotropically cross-linked alginate for the use as controlled drug-releasing matrices. In the current chapter, a comprehensive review on OkG–alginate composite beads in controlled drug release is presented.