Structure-based virtual screening of FDA-approved drugs to discover potential inhibitors of phosphoinositide kinase, PIKfyve.

The phosphoinositide kinase, PIKfyve is a lipid kinase that plays a vital role in membrane trafficking, endosomal transport, retroviral budding, and toll-like receptor signaling. Thus, it has emerged as a potential therapeutic target for several diseases, including, cancer, viral infections, and autoimmune diseases. However, a limited number of PIKfyve inhibitors have been reported so far.

Structure-Based Virtual Screening and Biological Characterization of Novel BACE-1 and Amyloid-β Aggregation Inhibitors.

Alzheimer's disease (AD) is a complex neurodegenerative disorder having limited treatment options. The beta-site APP cleaving enzyme 1 (BACE-1) is a key target for therapeutic intervention in Alzheimer's disease. To discover new scaffolds for BACE-1 inhibitors, a ChemBridge DIVERSet library of 20,000 small molecules was employed to structure-based virtual screening.

Medicinal chemistry-based perspectives on thiophene and its derivatives: exploring structural insights to discover plausible druggable leads.

Thiophene is a privileged pharmacophore in medicinal chemistry owing to its diversified biological attributes. The thiophene moiety has been ranked 4th in the US FDA drug approval of small drug molecules, with around 7 drug approvals over the last decade. The present review covers USFDA-approved drugs possessing a thiophene ring system.

A perspective on the development of small molecular neprilysin inhibitors (NEPi) with emphasis on cardiorenal disease.

Neprilysin is a cell surface metallo-endopeptidase, commonly identified as neutral endopeptidase (NEP), that plays a crucial role in the cleavage of peptides, for example, natriuretic peptides, angiotensin II, enkephalins, endothelin, bradykinin, substance P, glucagon-like peptide and amyloid beta. In the case of heart failure, a significant upsurge in NEP activity and expression enhances the degradation of natriuretic peptides. Therefore, NEP inhibitors have gained attention in the field of cardiology.

Design, synthesis, , and evaluation of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide derivatives as AChE/BACE 1 dual inhibitors.

Alzheimer's disease (AD) manifests as a progressive decline in cognitive function and mental behavior. Targeting two crucial enzymes associated with AD, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), in combination, holds promise for therapeutic breakthroughs. In this study, 40 derivatives of pyrrol-2-yl-phenyl allylidene hydrazine carboximidamide were designed based on prior research.

Unveiling the potential of novel indol-3-yl-phenyl allylidene hydrazine carboximidamide derivatives as AChE/BACE 1 dual inhibitors: a combined , synthesis and study.

Considering the failure of many enzyme inhibitors for Alzheimer's disease (AD), research is now focused on multi-target directed drug discovery. In this paper, inhibition of two essential enzymes implicated in AD pathologies, acetylcholinesterase (AChE) and BACE 1 (Beta-site APP Cleaving Enzyme), has been explored. Taking clues from our previous work, 41 novel indol-3-yl phenyl allylidene hydrazine carboximidamide derivatives were synthesized.

A structure-based pharmacophore modelling approach to identify and design new neprilysin (NEP) inhibitors: An in silico-based investigation.

Neutral endopeptidase or neprilysin (NEP) cleaves the natriuretic peptides, bradykinin, endothelin, angiotensin II, amyloid β protein, substance P, etc., thus modulating their effects on heart, kidney, and other organs. NEP has a proven role in hypertension, heart disease, renal disease, Alzheimer's, diabetes, and some cancers.

Network pharmacology combined with molecular docking and dynamics to assess the synergism of esculetin and phloretin against acute kidney injury-diabetes comorbidity.

Acute kidney injury (AKI) is a global health concern with high incidence and mortality, where diabetes further worsens the condition. The available treatment options are not uniformly effective against the complex pathogenesis of AKI-diabetes comorbidity. Hence, combination therapies based on the multicomponent, multitarget approach can tackle more than one pathomechanism and can aid in AKI-diabetes comorbidity management.

Renoprotective effect of esculetin against ischemic acute kidney injury-diabetic comorbidity.

Mitophagy maintains cellular homeostasis by eliminating damaged mitochondria. Accumulated damaged mitochondria can lead to oxidative stress and cell death. Induction of the PINK1/Parkin-mediated mitophagy is reported to be renoprotective in acute kidney injury (AKI).

Bioactivity predictions and virtual screening using machine learning predictive model.

Recently, there has been significant attention on machine learning algorithms for predictive modeling. Prediction models for enzyme inhibitors are limited, and it is essential to account for chemical biases while developing them. The lack of repeatability in available models and chemical bias issues constrain drug discovery and development.

Targeting the epigenetic reader "BET" as a therapeutic strategy for cancer.

Bromodomain and extraterminal (BET) proteins have the ability to bind to acetylated lysine residues present in both histones and non-histone proteins. This binding is facilitated by the presence of tandem bromodomains. The regulatory role of BET proteins extends to chromatin dynamics, cellular processes, and disease progression.

Progress in discovery and development of natural inhibitors of histone deacetylases (HDACs) as anti-cancer agents.

The study of epigenetic translational modifications had drawn great interest for the last few decades. These processes play a vital role in many diseases and cancer is one of them. Histone acetyltransferase (HAT) and histone deacetylases (HDACs) are key enzymes involved in the acetylation and deacetylation of histones and ultimately in post-translational modifications.

Discovery of blood-brain barrier permeable and orally bioavailable caffeine-based amide derivatives as acetylcholinesterase inhibitors.

Caffeine is one of the privileged natural products that shows numerous effects on the central nervous system. Herein, thirty-one caffeine-based amide derivatives were synthesized and evaluated in vitro for their anticholinesterase activity. The introduction of the amide group to the caffeine core augmented its anticholinesterase activity from an IC value of 128 to 1.

Nutraceuticals and network pharmacology approach for acute kidney injury: A review from the drug discovery aspect.

Acute kidney injury (AKI) has become a global health issue, with ∼12 million reports yearly, resulting in a persistent increase in morbidity and mortality rates. AKI pathophysiology is multifactorial involving oxidative stress, mitochondrial dysfunction, epigenetic modifications, inflammation, and eventually, cell death. Hence, therapies able to target multiple pathomechanisms can aid in AKI management.

Methoxy-naphthyl-Linked -Benzyl Pyridinium Styryls as Dual Cholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Structure-Activity Relationship.

The multifaceted nature of Alzheimer's disease (AD) indicates the need for multitargeted agents as potential therapeutics. Both cholinesterases (ChEs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), play a vital role in disease progression. Thus, inhibiting both ChEs is more beneficial than only one for effectively managing AD.

Design, Synthesis, and Pharmacological Evaluation of Embelin-Aryl/alkyl Amine Hybrids as Orally Bioavailable Blood-Brain Barrier Permeable Multitargeted Agents with Therapeutic Potential in Alzheimer's Disease: Discovery of SB-1448.

The complex and multifaceted nature of Alzheimer's disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Burm f., one of the oldest herbs in Indian traditional medicine.

A perspective on oligonucleotide therapy: Approaches to patient customization.

It is estimated that the human genome encodes 15% of proteins that are considered to be disease-modifying. Only 2% of these proteins possess a druggable site that the approved clinical candidates target. Due to this disparity, there is an immense need to develop therapeutics that may better mitigate the disease or disorders aroused by non-druggable and druggable proteins or enzymes.

Design, Synthesis and Evaluation of 2,4,6-substituted Pyrimidine Derivatives as BACE-1 Inhibitor: Plausible Lead for Alzheimer's Disease.

Unlabelled: Alzheimer's disease is one of the most common neurodegenerative disorder afflicting a large mass of population. BACE-1 (β-secretase) is an aspartyl protease of the amyloidogenic pathway considered responsible for Alzheimer's disease (AD). Since it catalyzes the rate-limiting step of Aβ-42 production from amyloid precursor protein (APP), its inhibition is considered a viable therapeutic strategy.

Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors.

Glycogen Synthase Kinase 3 (GSK3) is one of the Serine/Threonine protein kinases, which has gained a lot of attention for its role in a variety of pathways. It has two isoforms, GSK3α and GSK3β. However, GSK3β is highly expressed in different areas of the brain and has been implicated in Alzheimer's disease as it is involved in tau phosphorylation.

Peptides, Peptidomimetics, and Carbohydrate-Peptide Conjugates as Amyloidogenic Aggregation Inhibitors for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for 60-80% of dementia cases. For many years, AD causality was attributed to amyloid-β (Aβ) aggregated species. Recently, multiple therapies that target Aβ aggregation have failed in clinical trials, since Aβ aggregation is found in AD and healthy patients.

Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors.

Epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show excellent clinical efficacy for patients with non-small cell lung cancer (NSCLC) with EGFR mutations, including Exon 19 deletion and single-point substitution, and L858R of exon 21. The reason for the reduction in effectiveness of these EGFR TKIs is the T790M gatekeeper mutation in the ATP-binding pocket of Exon 20, which increases the affinity of EGFR for ATP. Newer EGFR TKIs, such as afatinib, osimertinib, rociletinib, EGF816 and ASP8273, selectively target T790M mutants, sparing wild-type EGFR.

Dynamin Functions and Ligands: Classical Mechanisms Behind.

Dynamin is a GTPase that plays a vital role in clathrin-dependent endocytosis and other vesicular trafficking processes by acting as a pair of molecular scissors for newly formed vesicles originating from the plasma membrane. Dynamins and related proteins are important components for the cleavage of clathrin-coated vesicles, phagosomes, and mitochondria. These proteins help in organelle division, viral resistance, and mitochondrial fusion/fission.

Design, synthesis and in vitro evaluation studies of sulfonyl-amino-acetamides as small molecule BACE-1 inhibitors.

The identification of a series of sulfonyl-amino-acetamides as BACE-1 (β-secretase) inhibitors for the treatment of Alzheimer's disease is reported. The derivatives were designed based on the docking simulation study, synthesized and assessed for BACE-1 inhibition in vitro. The designed ligands revealed desired binding interactions with the catalytic aspartate dyad and occupance of S1 and S2' active site regions.

Rational design, synthesis and in vitro evaluation of allylidene hydrazinecarboximidamide derivatives as BACE-1 inhibitors.

BACE-1 (β-secretase) is considered to be one of the promising targets for treatment of Alzheimer's disease as it catalyzes the rate limiting step of Aβ-42 production. Herein, we report a novel class of allylidene hydrazinecarboximidamide derivatives as moderately potent BACE-1 inhibitors, having aminoguanidine substitution on allyl linker with two aromatic groups on either side. A library of derivatives was designed based on the docking studies, synthesized and evaluated for BACE-1 inhibition in vitro.

QSAR and Docking Studies of N-hydroxy Urea Derivatives as Flap Endonuclease-1 Inhibitors.

Flap endonuclease-I (FEN-1) is involved in DNA repair and considered to be a novel target for the development of anticancer agents. N-hydroxy urea derivatives have been reported as FEN-1 inhibitors. To derive in vitro and in silico correlation, we have performed 2D-quantitative structure activity relationship (QSAR) analysis and docking studies on these compounds.