Designing of xanthine-based DPP-4 inhibitors: a structure-guided alignment dependent Multifacet 3D-QSAR modeling, and molecular dynamics simulation study.

The DPP-4 enzyme degrades incretin hormones GLP-1 and GIP. DPP-4 inhibitors are found effective in the prevention of the degradation of incretins. Xanthine scaffold-bearing molecules are reported as potential DPP-4 inhibitors for treating type 2 diabetes mellitus, e.g. the marketed drug linagliptin. In this work, structure-guided alignment-dependent atom- and Gaussian field-based 3D-QSAR have been performed on a dataset of 75 molecules. The robustness and predictive ability of the developed multifacet 3D-QSAR models were validated on different statistical parameters and found to be statistically fit. The favorable and unfavorable pharmacophoric features were mapped for each multifacet 3D-QSAR model based on three alignment sets (1-3). A five-point common pharmacophore hypothesis was generated separately for each set of alignments. The molecular dynamics simulations (up to 100 ns) were performed for the potent molecule from each alignment set (Compounds 12, 40 and 57) compared to reference standard linagliptin to study the binding energy and stability of target-ligand complexes. The MM-PBSA calculations revealed that the binding free energy and stability of compounds 12 (-40.324 ± 17.876 kJ/mol), 40 (-80.543 ± 21.782 kJ/mol) and 57 (-50.202 ± 16.055 kJ/mol) were better than the reference drug linagliptin (-20.390 ± 63.200 kJ/mol). The generated contour maps from structure-guided alignment-dependent multifacet 3D-QSAR models offer information about the structure-activity relationship (SAR) and ligand-target binding energy and stability data from MD simulation may be utilized to design and develop target selective xanthine-based novel DPP-4 inhibitors.Communicated by Ramaswamy H. Sarma.

Fyn, Blk, and Lyn kinase inhibitors: A mini-review on medicinal attributes, research progress, and future insights.

Fyn, Blk, and Lyn are part of a group of proteins called Src family kinases. They are crucial in controlling cell communication and their response to the growth, changes, and immune system. Blocking these proteins with inhibitors can be a way to treat diseases where these proteins are too active. The primary mode of action of these inhibitors is to inhibit the phosphorylation of Fyn, Blk, and Lyn receptors, which in turn affects how signals pass within the cells. This review shows the structural and functional aspects of Fyn, Blk, and Lyn kinases, highlighting the significance of their dysregulation in diseases such as cancer and autoimmune disorders. The discussion encompasses the design strategies, SAR analysis, and chemical characteristics of effective inhibitors, shedding light on their specificity and potency. Furthermore, it explores the progress of clinical trials of these inhibitors, emphasizing their potential therapeutic applications.

Targeting JAK2/STAT3 for the treatment of cancer: A review on recent advancements in molecular development using structural analysis and SAR investigations.

Cancer is indeed considered a hazardous and potentially life-threatening disorder. The JAK/STAT pathway is an important intracellular signaling cascade essential for many physiological functions, such as immune response, cell proliferation, and differentiation. Dysregulation of this pathway aids in the progression and development of cancer. The downstream JAK2/STAT3 signaling cascades are legitimate targets against which newer anticancer drugs can be developed to prevent and treat cancer. Understanding the mechanisms behind JAK2/STAT3 participation in cancer has paved the way for developing innovative targeted medicines with the potential to improve cancer treatment outcomes. This article provides information on the current scenario and recent advancements in the design and development of anticancer drugs targeting JAK2/STAT3, including structural analysis and SAR investigations of synthesized molecules. Numerous preclinical and clinical trials are ongoing on these inhibitors, which are highlighted to gain more insight into the broader development prospects of inhibitors of JAK2/STAT3.

An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021).

New drugs being established in the market every year produce specified structures for selective biological targeting. With medicinal insights into molecular recognition, these begot molecules open new rooms for designing potential new drug molecules. In this review, we report the compilation and analysis of a total of 56 drugs including 33 organic small molecules (Mobocertinib, Infigratinib, Sotorasib, Trilaciclib, Umbralisib, Tepotinib, Relugolix, Pralsetinib, Decitabine, Ripretinib, Selpercatinib, Capmatinib, Pemigatinib, Tucatinib, Selumetinib, Tazemetostat, Avapritinib, Zanubrutinib, Entrectinib, Pexidartinib, Darolutamide, Selinexor, Alpelisib, Erdafitinib, Gilteritinib, Larotrectinib, Glasdegib, Lorlatinib, Talazoparib, Dacomitinib, Duvelisib, Ivosidenib, Apalutamide), 6 metal complexes (Edotreotide Gallium Ga-68, fluoroestradiol F-18, Cu 64 dotatate, Gallium 68 PSMA-11, Piflufolastat F-18, 177Lu (lutetium)), 16 macromolecules as monoclonal antibody conjugates (Brentuximabvedotin, Amivantamab-vmjw, Loncastuximabtesirine, Dostarlimab, Margetuximab, Naxitamab, Belantamabmafodotin, Tafasitamab, Inebilizumab, SacituzumabGovitecan, Isatuximab, Trastuzumab, Enfortumabvedotin, Polatuzumab, Cemiplimab, Mogamulizumab) and 1 peptide enzyme (Erwiniachrysanthemi-derived asparaginase) approved by the U.S. FDA between 2018 to 2021. These drugs act as anticancer agents against various cancer types, especially non-small cell lung, lymphoma, breast, prostate, multiple myeloma, neuroendocrine tumor, cervical, bladder, cholangiocarcinoma, myeloid leukemia, gastrointestinal, neuroblastoma, thyroid, epithelioid and cutaneous squamous cell carcinoma. The review comprises the key structural features, approval times, target selectivity, mechanisms of action, therapeutic indication, formulations, and possible synthetic approaches of these approved drugs. These crucial details will benefit the scientific community for futuristic new developments in this arena.

Microplastics in environment: a comprehension on sources, analytical detection, health concerns, and remediation.

Contamination of ecosystems by microplastics (MPs) has been reported intensively worldwide in the recent decade. A trend of reports indicated their presence in the atmosphere; food items and soil ecosystems are rising continuously. Literature evidenced that MPs are abundant in seawater, beach sand, drinking water, agricultural soils, wastewater treatment plant (WWTP) effluent, and the atmosphere. The greater abundance of MPs in the environment has led to their invasion of seafood, human-consumed food items such as table salts, beverages, takeout food containers, and disposable cups, marine biological lives, and creating serious health hazards in humans. Moreover, the absence of guidelines and specifications for controlling MPs in the environment makes the situation alarming, and the human toxicity data of MPs is scarce. Thereby, the toxicity assessment of MPs in humans is of greater concern. This review compiles the updated information on the potential sources of MPs in different components of the environment (viz. soil, water, and air), their analysis methods, effects on human health, and remediation methods.

A comprehension on structure guided alignment dependent 3D-QSAR modelling, and molecular dynamics simulation on 2,4-thiazolidinediones as aldose reductase inhibitors for the management of diabetic complications.

Aldose reductase is an oxo-reductase enzyme belonging to the aldo-keto reductase class. Compounds having thiazolidine-2,4-dione scaffold are reported as potential aldose reductase inhibitors for diabetic complications. The present work uses structure-guided alignment-dependent Gaussian field- and atom-based 3D-QSAR on a dataset of 84 molecules. 3D-QSAR studies on two sets of dataset alignment have been carried out to understand the favourable and unfavourable structural features influencing the affinity of these inhibitors towards the enzyme. Using common pharmacophore hypotheses, the five-point pharmacophores for aldose reductase favourable features were generated. The molecular dynamics simulations (up to 100 ns) were performed for the potent molecule from each alignment set (compounds 24 and 65) compared to reference standard tolrestat and epalrestat to study target-ligand complexes' binding energy and stability. Compound 65 was most stable with better interactions in the aldose reductase binding pocket than tolrestat. The MM-PBSA study suggests compound 65 possessed better binding energy than reference standard tolrestat, i.e. -87.437 ± 19.728 and -73.424 ± 12.502 kJ/mol, respectively. The generated 3D-QSAR models provide information about structure-activity relationships and ligand-target binding energy. Target-specific stability data from MD simulation would be helpful for rational compound design with better aldose reductase activity.Communicated by Ramaswamy H. Sarma.

An insight on medicinal attributes of 1,2,3- and 1,2,4-triazole derivatives as alpha-amylase and alpha-glucosidase inhibitors.

Diabetes Mellitus (DM) is the globe's common leading disease which is caused by high consumption of glucose. DM compiles groups of metabolic disorders which are characterized by inadequate secretion of insulin from pancreas, resulting in hyperglycemia condition. Many enzymes play a vital role in the metabolism of carbohydrate known as α-amylase and α-glucosidase which is calcium metalloenzyme that leads to breakdown of complex polysaccharides into glucose. To tackle this problem, search for newer antidiabetic drugs is the utmost need for the treatment and/or management of increasing diabetic burden. The inhibition of α-amylase and α-glucosidase is one of the effective therapeutic approaches for the development of antidiabetic therapeutics. The exhaustive literature survey has shown the importance of medicinally privileged triazole specifically 1,2,3-triazol and 1,2,4-triazoles scaffold tethered, fused and/or clubbed with other heterocyclic rings structures as promising agents for designing and development of novel antidiabetic therapeutics. Molecular hybrids namely pyridazine-triazole, pyrazoline-triazole, benzothiazole-triazole, benzimidazole-triazole, curcumin-triazole, (bis)coumarin-triazole, acridine-9-carboxamide linked triazole, quinazolinone-triazole, xanthone-triazole, thiazolo-triazole, thiosemicarbazide-triazole, and indole clubbed-triazole are few examples which have shown promising antidiabetic activity by inhibiting α-amylase and/or α-glucosidase. The present review summarizes the structure-activity relationship (SAR), enzyme inhibitory activity including IC50 values, percentage inhibition, kinetic studies, molecular docking studies, and patents filed of the both scaffolds as alpha-amylase and alpha-glucosidase inhibitors, which may be used for further development of potent inhibitors against both enzymes.

Current progress in the targeted therapy of breast cancer: Structure-activity correlation and docking studies (2015-2021).

Despite cancer research and therapy, breast cancer remains a complicated health crisis in women and represents a top biomedical research priority. Nowadays, breast cancer is an extremely heterogeneous disease and is known as the leading cause of death among women worldwide. The incidence and mortality rates of breast cancer have been increasing gradually for the past decades. Nowadays, common treatments for breast cancer are chemotherapy, endocrine therapy, immunotherapy, radiotherapy, and surgery. The most common targets in breast cancer treatment are human epidermal growth factor receptor 2 (HER2) and estrogen receptors. The literature suggests that several targets/pathways are also involved in the development of breast cancer, that is, poly(ADP-ribose) polymerase (PARP), bromodomain-containing protein 4 (BRD4), cyclin-dependent kinase 4/6 (CDK4/6), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), polo-like kinase 1 (PLK1), phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), histone deacetylase (HDAC), nuclear factor kappa B (NF-κB), PD-L1, and aromatase inhibitors. Meanwhile, the study of breast cancer is a hot topic in the current scenario of basic/clinical research. This review article provides information on different targets associated with breast cancer and summarizes the progress of current research on synthesized inhibitors as anti-breast cancer agents from 2015 to 2021. The review aims to provide structure-activity relationship and docking studies for designing novel compounds for breast cancer therapy.

Remediation of environmental toxicants using carbonaceous materials: opportunity and challenges.

Adsorption and photocatalytic properties of carbonaceous materials, viz., carbon nanotubes (CNTs), fullerene, graphene, graphene oxide, carbon nanofiber nanospheres, and activated carbon, are the legitimate weapons for the remediation of emerging and persistent inorganic/organic contaminants, heavy metals, and radionucleotides from the environment. High surface area, low or non-toxic nature, ease of synthesis, regeneration, and chemical modification of carbonaceous material make them ideal for the removal of toxicants. The research techniques investigated during the last decade for the elimination of environmental toxicants using carbonaceous materials are reviewed to offer comprehensive insight into the mechanism, efficiency, applications, advantages, and shortcomings. Opportunities and challenges associated with carbon materials have been discussed to suggest future perspectives in the remediation of environmental toxicants.

A comprehensive update on phytochemistry, analytical aspects, medicinal attributes, specifications and stability of stigmasterol.

Phytosterols are bioactive substances naturally found in plant cell membranes, and their chemical structure is comparable to cholesterol found in mammalian cells. They are widely distributed in plant foods like olive oil, nuts, seeds, and legumes. Amongst the variety of phytosterols, stigmasterol is the vital compound found abundantly in plants. Numerous hormones, including estrogen, progesterone, corticoids and androgen, are synthesized by stigmasterol. Multiple in-vitro and in-vivo investigations have shown that stigmasterol has various biological effects, including antioxidant, anticancer, antidiabetic, respiratory diseases, and lipid-lowering effects. Experimental research on stigmasterol provides indisputable proof that this phytosterol has the potential to be employed in supplements used to treat the illnesses mentioned above. This substance has a high potential, making it a noteworthy medication in the future. Although several researchers have investigated this phytosterol to assess its prospective qualities, it has not yet attained therapeutic levels, necessitating additional clinical studies. This review offers a comprehensive update on stigmasterol, including chemical framework, biosynthesis, synthetic derivatives, extraction and isolation, analytical aspects, pharmacological profile, patent status, clinical trials, stability and specifications as per regulatory bodies.

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.

Dual aromatase-steroid sulfatase inhibitors (DASI's) for the treatment of breast cancer: a structure guided ligand based designing approach.

Dual aromatase-steroid sulfatase inhibitors (DASIs) lead to significant deprivation of estrogen levels as compared to a single target inhibition and thereby exhibited an additive or synergistic effect in the treatment of hormone-dependent breast cancer (HDBC). Triazole-bearing DASI's having structural features of clinically available aromatase inhibitors are identified as lead structures for optimization as DASI's. To identify the spatial fingerprints of target-specific triazole as DASI's, we have performed molecular docking assisted Gaussian field-based comparative 3D-QSAR studies on a dataset with dual aromatase-STS inhibitory activities. Separate contours were generated for both aromatase and steroid sulphates showing respective pharmacophoric structural requirements for optimal activity. These developed 3D-QSAR models also showed good statistical measures with the excellent predictive ability with PLS-generated validation constraints. Comparative steric, electrostatic, hydrophobic, HBA, and HBD features were elucidated using respective contour maps for selective target-specific favourable activity. Furthermore, the molecular docking was used for elucidating the mode of binding as DASI's along with the MD simulation of 100 ns revealed that all the protease-ligand docked complexes are overall stable as compared to reference ligand (inhibitor ASD or Irosustat) complex. Further, the MM-GBSA study revealed that compound 24 binds to aromatase as well as STS active site with relatively lower binding energy than reference complex, respectively. A comparative study of these developed multitargeted QSAR models along with molecular docking and dynamics study can be employed for the optimization of drug candidates as DASI's.Communicated by Ramaswamy H. Sarma.

Convolutions in the rendition of nose to brain therapeutics from bench to bedside: Feats & fallacies.

Brain, a subtle organ of multifarious nature presents plethora of physiological, metabolic and bio-chemical convolutions that impede the delivery of biomolecules and thereby resulting in truncated therapeutic outcome in pathological conditions of central nervous system (CNS). The absolute bottleneck in the therapeutic management of such devastating CNS ailments is the BBB. Another pitfall is the lack of efficient technological platforms (due to high cost and low approval rates) as well as limited clinical trials (due to failures of neuro­leads in late-stage pipelines) for CNS disorders which has become a literal brain drain with poorest success rates compared to other therapeutic areas, owing to time consuming processes, tremendous convolutions and conceivable adverse effects. With the advent of intranasal delivery (via direct N2B or indirect nose to blood to brain), several novel drug delivery carriers viz. unmodified or surface modified nanoparticle based carriers, lipid based colloidal nanocarriers and drysolid/liquid/semisolid nanoformulations or delivery platforms have been designed as a means to deliver therapeutic agents (small and large molecules, peptides and proteins, genes) to brain, bypassing BBB for disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, schizophrenia and CNS malignancies primarily glioblastomas. Intranasal application offers drug delivery through both direct and indirect pathways for the peripherally administered psychopharmacological agents to CNS. This route could also be exploited for the repurposing of conventional drugs for new therapeutic uses. The limited clinical translation of intranasal formulations has been primarily due to existence of barriers of mucociliary clearance in the nasal cavity, enzyme degradation and low permeability of the nasal epithelium. The present review literature aims to decipher the new paradigms of nano therapeutic systems employed for specific N2B drug delivery of CNS drugs through in silico complexation studies using rationally chosen mucoadhesive polymers (exhibiting unique physicochemical properties of nanocarrier's i.e. surface modification, prolonging retention time in the nasal cavity, improving penetration ability, and promoting brain specific delivery with biorecognitive ligands) via molecular docking simulations. Further, the review intends to delineate the feats and fallacies associated with N2B delivery approaches by understanding the physiological/anatomical considerations via decoding the intranasal drug delivery pathways or critical factors such as rationale and mechanism of excipients, affecting the permeability of CNS drugs through nasal mucosa as well as better efficacy in terms of brain targeting, brain bioavailability and time to reach the brain. Additionally, extensive emphasis has also been laid on the innovative formulations under preclinical investigation along with their assessment by means of in vitro /ex vivo/in vivo N2B models and current characterization techniques predisposing an efficient intranasal delivery of therapeutics. A critical appraisal of novel technologies, intranasal products or medical devices available commercially has also been presented. Finally, it could be warranted that more reminiscent pharmacokinetic/pharmacodynamic relationships or validated computational models are mandated to obtain effective screening of molecular architecture of drug-polymer-mucin complexes for clinical translation of N2B therapeutic systems from bench to bedside.

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.

2,4-Thiazolidinediones as PTP 1B Inhibitors: A Mini Review (2012-2018).

2,4-thiazolidinedione (TZD) scaffold is a synthetic versatile scaffold explored by medicinal chemists for the discovery of novel molecules for the target-specific approach to treat or manage number of deadly ailments. PTP 1B is the negative regulator of insulin signaling cascade, and its diminished activity results in abolishment of insulin resistance associated with T2DM. The present review focused on the seven years journey (2012-2018) of TZDs as PTP 1B inhibitors with the insight into the amendments in the structural framework of TZD scaffold in order to optimize/design potential PTP 1B inhibitors. We have investigated the synthesized molecules based on TZD scaffold with potential activity profile against PTP 1B. Based on the SAR studies, the combined essential pharmacophoric features of selective and potent TZDs have been mapped and presented herewith for further design and synthesis of novel inhibitors of PTP 1B. Compound 46 bearing TZD scaffold with N-methyl benzoic acid and 5-(3-methoxy-4-phenethoxy) benzylidene exhibited the most potent activity (IC50 1.1 µM). Imidazolidine-2,4-dione, isosteric analogue of TZD, substituted with 1-(2,4-dichlorobenzyl)-5-(3-(2,4- dichlorobenzyloxy)benzylidene) (Compound 15) also endowed with very good PTP inhibitory activity profile (IC50 0.57 µM). It is noteworthy that Z-configuration is essential in structural framework around the double bond of arylidene for the designing of bi-dentate ligands with optimum activity.

Structure based comprehensive modelling, spatial fingerprints mapping and ADME screening of curcumin analogues as novel ALR2 inhibitors.

Aldose reductase (ALR2) inhibition is the most legitimate approach for the management of diabetic complications. The limited triumph in the drug development against ALR2 is mainly because of its close structural similarity with the other members of aldo-keto reductase (AKR) superfamily viz. ALR1, AKR1B10; and lipophilicity problem i.e. poor diffusion of synthetic aldose reductase inhibitors (ARIs) to target tissues. The literature evidenced that naturally occurring curcumin demonstrates relatively specific and non-competitive inhibition towards human recombinant ALR2 over ALR1 and AKR1B10; however ß-diketone moiety of curcumin is a specific substrate for liver AKRs and accountable for it's rapid in vivo metabolism. In the present study, structure based comprehensive modelling studies were used to map the pharmacophoric features/spatial fingerprints of curcumin analogues responsible for their ALR2 specificity along with potency on a data set of synthetic curcumin analogues and naturally occurring curcuminoids. The data set molecules were also screened for drug-likeness or ADME parameters, and the screening data strongly support that curcumin analogues could be proposed as a good drug candidate for the development of ALR2 inhibitors with improved pharmacokinetic profile compared to curcuminoids due to the absence of ß-diketone moiety in their structural framework.