Etodolac utility in osteoarthritis: drug delivery challenges, topical nanotherapeutic strategies and potential synergies.

Osteoarthritis (OSA) is a prevalent joint disorder characterized by losing articular cartilage, primarily affecting the hip, knee and spine joints. The impact of OSA offers a major challenge to health systems globally. Therapeutic approaches encompass surgical interventions, non-pharmacological therapies (exercise, rehabilitation, behavioral interventions) and pharmacological treatments.

Evaluation of steroids as anti-inflammatory agents to combat the Covid-19 cytokine storm: a bioinformatics and structure-based drug designing approach.

Since the SARS-CoV-2 epidemic, researchers have been working on figuring out ways to tackle multi-organ failure and hyperinflation, which are brought on by a cytokine storm. Angiotensin-converting enzyme 2 (ACE2), a SARS-CoV-2 spike glycoprotein's cellular receptor, is involved in complicated molecular processes that result in hyperinflammation. is one of the traditional Chinese medicines that is used as an immune booster, and it has exhibited efficacy in lowering blood glucose levels, seminal emissions, and infertility.

Identification of natural peptides from "PlantPepDB" database as anti-SARS-CoV-2 agents: A protein-protein docking approach.

Background: A global pandemic owing to COVID-19 infection has created havoc in the entire world. The etiological agent responsible for this viral outbreak is classified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Still, there's no specific drug or preventive medication to treat SARS-CoV-2.

Role of Genetic Polymorphisms in Drug-Metabolizing Enzyme-Mediated Toxicity and Pharmacokinetic Resistance to Anti-Cancer Agents: A Review on the Pharmacogenomics Aspect.

The inter-individual differences in cancer susceptibility are somehow correlated with the genetic differences that are caused by the polymorphisms. These genetic variations in drug-metabolizing enzymes/drug-inactivating enzymes may negatively or positively affect the pharmacokinetic profile of chemotherapeutic agents that eventually lead to pharmacokinetic resistance and toxicity against anti-cancer drugs. For instance, the CYP1B1*3 allele is associated with CYP1B1 overexpression and consequent resistance to a variety of taxanes and platins, while 496T>G is associated with lower levels of dihydropyrimidine dehydrogenase, which results in severe toxicities related to 5-fluorouracil.

Network Analysis Guided Designing of Multi-Targeted Anti-Fungal Agents: Synthesis and Biological Evaluation.

During the ongoing pandemic, there have been increasing reports of invasive fungal disease (IFD), particularly among immunocompromised populations. is one of the most common clinical pathogenic microorganisms which have become a serious health threat to population either infected with Covid-19 or on treatment with immunosuppressant's/broad-range antibiotics. Currently, benzothiazole is a well explored scaffold for anti-fungal activity, especially mercapto substituted benzothiazoles.

Hydantoin based dual inhibitors of ALR2 and PARP-1: Design, synthesis, in-vitro and in-vivo evaluation.

Diabetic nephropathy is one of the most dreadful diabetic complications (DCs). The polyol pathway and unified mechanism are two important pathways implicated in the progression of DCs. In this regard, targeting the key enzymes i.

Identification of missense SNP-mediated mutations in the regulatory sites of aldose reductase (ALR2) responsible for treatment failure in diabetic complications.

Scientific pieces of evidence indicate that the polymorphism in the ALR2 regulatory gene favors the susceptibility to diabetic complications (DCs). Previous studies have uncovered several single nucleotide polymorphisms (SNPs) in the ALR2 regulatory sites that negatively modulate the activity of this enzyme and eventually increase the risks of DCs. In view of this, the current study aimed at investigating whether the mutation as a resultant of missense SNPs in the regulatory site of ALR2 enzyme can also hamper the interactions of ALR2 inhibitors with the key amino acid residues in the ALR2 binding site.

Functional relationship of SNP (Ala490Thr) of an epigenetic gene results in the progression and poor survival of ER+/tamoxifen treated breast cancer patients.

is a classic histone methyltransferase that causes the trimethylation of and consequently suppresses the cancer preventive genes. The role of elevated levels of EZH2 expression in breast cancer aggressiveness and poor prognosis is very well established. The present study focusses on the insight of the clinically important SNPs of gene in determining the structure-function relationship towards breast cancer susceptibility.

Von Willebrand factor: A key glycoprotein involved in thrombo-inflammatory complications of COVID-19.

COVID-19 is an ongoing public health emergency that has affected millions of people worldwide and is still a threat to many more. One of the pathophysiological features of COVID-19 is associated with the activation of vascular endothelial cells (ECs) leading to the disruption of vascular integrity, coagulation and inflammation. An interlink mechanism between coagulation and inflammatory pathways has been reported in COVID-19.

Identification of kinase inhibitors that rule out the CYP27B1-mediated activation of vitamin D: an integrated machine learning and structure-based drug designing approach.

CYP27B1, a cytochrome P450-containing hydroxylase enzyme, converts vitamin D precursor calcidiol (25-hydroxycholecalciferol) to its active form calcitriol (1α,25(OH)D). Tyrosine kinase inhibitor such as imatinib is reported to interfere with the activation of vitamin D by inhibiting CYP27B1 enzyme. Consequently, there is a decrease in the serum levels of active vitamin D that in turn may increase the relapse risk among the cancer patients treated with imatinib.

Benzimidazole based hybrids against complex diseases: A catalogue of the SAR profile.

The fused heterocyclic ring system has been recognized as a privileged structure that is used as a template in medicinal chemistry for drug discovery. Benzimidazole is one of the common scaffolds found in several natural products such as histidine, purines, and an integral part of vitamin B12. This hetero-aromatic bicyclic ring system acts as a pharmacophore in various drugs of therapeutic interest and has a broad spectrum of activity.

Molecular modeling approaches to address drug-metabolizing enzymes (DMEs) mediated chemoresistance: a review.

Resistance against clinically approved anticancer drugs is the main roadblock in cancer treatment. Drug metabolizing enzymes (DMEs) that are capable of metabolizing a variety of xenobiotic get overexpressed in malignant cells, therefore, catalyzing drug inactivation. As evident from the literature reports, the levels of DMEs increase in cancer cells that ultimately lead to drug inactivation followed by drug resistance.

Virtual screening of epalrestat mimicking selective ALR2 inhibitors from natural product database: auto pharmacophore, ADMET prediction and molecular dynamics approach.

Epalrestat is the only effective aldose reductase (ALR2) inhibitor available in the market for the treatment of diabetic neuropathy. Clinical effectiveness of epalrestat in diabetic neuropathy encouraged us to develop some more ALR2 inhibitors with a better therapeutic profile. Herein, we utilized the pharmacophoric features of epalrestat to search some novel ALR2 inhibitors from an InterBioScreen database of natural compounds.

QM/MM analysis, synthesis and biological evaluation of epalrestat based mutual-prodrugs for diabetic neuropathy and nephropathy.

Herein, a quantum mechanics/molecular mechanics (QM/MM) based biotransformation study was performed on synthetically feasible mutual-prodrugs of epalrestat which have been identified from an in-house database developed by us. These prodrugs were submitted to quantum polarized ligand docking (QPLD) with the CES1 enzyme followed by MM-GBSA calculation. Electronic aspects of transition state of these prodrugs were also considered to study the catalytic process through density functional theory (DFT).

The interplay between inflammatory pathways and COVID-19: A critical review on pathogenesis and therapeutic options.

COVID-19, caused by SARS-CoV-2, emerged as the deadliest outbreak that has now become a serious health issue to mankind. Activation of inflammatory signaling pathways and cytokine storm are crucial factors that lead to acute respiratory distress syndrome (ARDS) in COVID-19 patients. Excessive secretion of pro-inflammatory cytokines and chemokines leads to the dysregulation of the innate immune system.

Scaffold morphing of arbidol (umifenovir) in search of multi-targeting therapy halting the interaction of SARS-CoV-2 with ACE2 and other proteases involved in COVID-19.

The rapid emergence of novel coronavirus, SARS-coronavirus 2 (SARS-CoV-2), originated from Wuhan, China, imposed a global health emergency. Angiotensin-converting enzyme 2 (ACE2) receptor serves as an entry point for this deadly virus while the proteases like furin, transmembrane protease serine 2 (TMPRSS2) and 3 chymotrypsin-like protease (3CLpro) are involved in the further processing and replication of SARS-CoV-2. The interaction of SP with ACE2 and these proteases results in the SARS-CoV-2 invasion and fast epidemic spread.

Addressing selectivity issues of aldose reductase 2 inhibitors for the management of diabetic complications.

Aldose Reductase 2 (ALR2), the rate-limiting enzyme of the polyol pathway, plays an important role in detoxification of some toxic aldehydes. Under hyperglycemia, this enzyme overactivates and causes diabetic complications (DC). Therefore, ALR2 inhibition has been established as a potential approach to manage these complications.

Structural investigation on the selective COX-2 inhibitors mediated cardiotoxicity: A review.

Initially, the selective COX-2 inhibitors were developed as safer alternatives to the conventional NSAIDs, but later on, most of them were withdrawn from the market due to the risk of heart attack and stroke. Celecoxib, the first selective COX-2 inhibitor, was approved by the Food and Drug Administration (FDA) in December 1998 and was taken back from the market in 2004. Since then, many coxibs have been discontinued one by one due to adverse cardiovascular events.

Phytochemical Screening, Cytotoxicity and Anti-inflammatory Activities of the Leaf Extracts from of Indian Origin to Explore their Potential for Medicinal Uses.

Background: Lawsonia inermis Linn popularly known as Henna, plays an important role in ayurvedic or natural herbal medicines. The presence of phytoconstituents in henna, that may affect the animal or human health adversely, needs to be elucidated for L. inermis Linn species grown in India.

Pharmacophore-based designing of putative ROS-1 targeting agents for NSCLC.

Non-small cell lung cancer (NSCLC) is a fatal non-immunogenic malignancy, and proto-oncogene receptor tyrosine kinase (ROS-1) is one of its clinically relevant biomarkers. In this context, herein, we report a series of benzimidazol-2-amine derivatives which were synthesized on the basis of the pharmacophore of ROS-1 and evaluated for anti-proliferative activity. For this, the in silico receptor-ligand pharmacophore model of ROS-1, previously published by our own group, was utilized to screen out an in-house database of small molecule heterocycles.

Search for non-acidic ALR2 inhibitors: Evaluation of flavones as targeted agents for the management of diabetic complications.

Diabetic complications (DC) follow multiple pathophysiological pathways and one of the key pathways is the polyol pathway which involves the metabolism of glucose via aldose reductase (ALR2) and sorbitol dehydrogenase (SDH). ALR2 inhibitors such as epalrestat has already been established as promising candidates for the management of DC. On the basis of pathophysiological understanding of polyol pathway, simultaneous inhibition of ALR2 and SDH may be expected to provide synergistic outcomes in the treatment strategies for DC.

Bio-Inspired Strategies against Diabetes and Associated Complications: A Review.

Bio-molecules are the most important target to be considered while designing any drug delivery system. The logic lies in using such bio-sensing or bio-mimicking systems in their formulations that can mimic the active site of those receptors to which the drug is going to bind. Polymers mimicking the active site of target enzymes are regarded as bio-inspired polymers and can be used to ameliorate many diseased conditions.

Butterfly structure: a scaffold of therapeutic importance.

Graphical abstract [Formula: see text].

hCES1 and hCES2 mediated activation of epalrestat-antioxidant mutual prodrugs: Unwinding the hydrolytic mechanism using in silico approaches.

Herein, we report four series of mutual prodrugs of epalrestat by combining it with different antioxidants using glycine, beta-alanine, and phenylalanine as a linker and by directly linking them through an ester linkage. The designed prodrugs were subjected to pharmacophore and docking-based virtual screening to determine the susceptibility of these prodrugs to be hydrolyzed by human carboxylesterases (hCES1 and hCES2). Five best prodrugs from each series were further submitted to detailed mechanistic study of hCES1 and hCES2 based hydrolytic activation using quantum mechanics and molecular dynamics approach.

Drug metabolizing enzymes-associated chemo resistance and strategies to overcome it.

Regardless of continuous research to develop effective chemotherapies and improve patient's prognosis, cancer still remains one of the most deadly diseases worldwide. The reduction in the pace of successfully developing an effective anti-cancer drug is due to the rapid emergence of drug resistance exhibited by tumor cells. One of the resistance mechanisms which is least considered and somewhat overlooked is chemoresistance via drug metabolizing enzymes (DMEs).