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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. Cordyceps militaris 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. In the current study, we explored the potential of Cordyceps militaris steroids as key agents in managing the anger of cytokine storm in Covid-19 using network ethnopharmacological techniques and structure-based drug designing approaches. The steroids present in Cordyceps militaris were initially screened against the targets involved in inflammatory pathways. The results revealed that out of 16 steroids, 5 may be effective against 17 inflammatory pathways by targeting 11 pathological proteins. Among the five steroids, beta-sitosterol, Cholest-5-en-3β-ol, 3β, and 7α-Dihydroxycholest-5-ene were found to interact with thrombin (F2), an important protein reported to reduce the severity of inflammatory mediators and Cholest-4-en-3-one was found to target Glucocorticoid receptor (NR3C1). The top docked steroid displayed key interactions with both targets, which retained key interactions throughout the 100 ns simulation period. These compounds were also shown high binding free energy scores in water swap studies. Based on obtained results the current study suggests the use of Cordyceps militaris as an add-on therapy that may reduce the progression of inflammatory co-morbidities among patients infected with SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

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. This study was designed to demonstrate the efficacy of some anti-viral peptides obtained from a plant database i.e., PlantPepDB as potential ACE-2-Spike (S) protein complex neutralizers using a structure-based drug designing approach., Method: A total of 83 anti-viral plant peptides were screened from a peptide database i.e. PlantPepDB based on their reported anti-viral activities against various viral strains. In order to screen peptides that may potentially interfere with ACE-2 and S complex formation, molecular docking studies were conducted using the flare module of Cresset software and subsequently, analysed the crucial interactions between the peptides and S complexes and ACE-2/S complex. Herein, the interactions and docking scores obtained for ACE-2/S complex were considered as references. The S-peptides complexes which displayed superior interactions and docking scores than reference complex i.e., ACE2-S were considered as final hits. The Molecular dynamics studies were conducted for a period of 30 ns for each of the final hit/S complex to understand the interaction stability and binding mechanism of designed peptides., Results: The molecular docking results revealed that five peptides including Cycloviolacin Y3, Cycloviolacin Y1, White cloud bean defensin, Putative defensin 3.1, and Defensin D1 showed superior docking scores (i.e. -1372.5 kJ/mol to -1232.6 kJ/mol) when docked at the ACE2 binding site of S-protein than score obtained for the complex of ACE-2 and S protein i.e. -1183.4 kJ/mol. Moreover, these top five peptides manifested key interactions required to prevent the binding of S protein with ACE2. The molecular dynamics simulation study revealed that two of these five peptides i.e. Cycloviolacin Y3 and Cycloviolacin Y1 displayed minimal RMSD fluctuations., Conclusions: The current structure-based drug-designing approach shows the possible role of anti-viral plant peptides as potential molecules to be explored at the initial stage of viral pathogenesis., Competing Interests: The author (s) declares no conflict of interest., (© 2023 Published by Elsevier B.V.)

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.e., aldose reductase (ALR2) and poly (ADP-ribose) polymerase-1 (PARP-1), of these pathways can be a relevant strategy. Thus, in this study, the pharmacophoric requirements necessary for the dual inhibition of these two enzymes i.e., ALR2 and PARP-1 were identified and consequently, some hydantoin based molecules were designed. The designed molecules were subjected to structure-based molecular modelling analysis including molecular docking analysis and molecular dynamic simulations. The promising molecules were duly synthesized and examined for their ALR2 and PARP-1 dual inhibitory activities and selectivity over aldehyde reductase (ALR1) using in vitro enzymatic assays. Based on the results of in silico analysis and in vitro assays, the best three molecules were evaluated in vivo for their nephroprotective effect and antioxidant potential in the high-fat diet-streptozotocin induced diabetic rat model. The results showed that the compounds FM6B, FM7B and FM9B were having low micromolar inhibitory potential against ALR2 (IC 50 ; 1.02, 1.14 and 1.08 μM, respectively) and PARP-1 (IC 50 ; 0.95, 0.81 and 1.42 μM, respectively) with selectivity over ALR1 (selectivity index; 43.63, 37.03 and 45.14, respectively)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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. In this context, a pharmacogenomics approach can be applied to ascertain the role of the genetic make-up in a person's response to any drug. This approach collectively utilizes pharmacology and genomics to develop effective and safe medications that are devoid of resistance problems. In addition, recently reported genomics studies revealed the impact of many single nucleotide polymorphisms in tumors. These studies emphasized the importance of single nucleotide polymorphisms in drug-metabolizing enzymes on the effect of anti-tumor drugs. In this review, we discuss the pharmacogenomics aspect of polymorphisms in detail to provide an insight into the genetic manipulations in drug-metabolizing enzymes that are responsible for pharmacokinetic resistance or toxicity against well-known anti-cancer drugs. Special emphasis is placed on different deleterious single nucleotide polymorphisms and their effect on pharmacokinetic resistance. The information provided in this report may be beneficial to researchers, especially those who are working in the field of biotechnology and human genetics, in rationally manipulating the genetic information of patients with cancer who are undergoing chemotherapy to avoid the problem of pharmacokinetic resistance/toxicity associated with drug-metabolizing enzymes., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

During the ongoing pandemic, there have been increasing reports of invasive fungal disease (IFD), particularly among immunocompromised populations. Candida albicans 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. It is reported that exploring the 2 nd position of benzothiazoles yield improved anti-fungal molecules. Therefore, in the current study, lead optimization approach using bioisosteric replacement protocol was followed to improve the anti-fungal activity of an already reported benzothiazole derivative, N -(1,3-benzothiazole-2-yl)-2-(pyridine-3-ylformohydrazido) acetamide. To rationally identify the putative anti-candida targets of this derivative, network analysis was carried out. Complexes of designed compounds and identified putative targets were further analyzed for the docking interactions and their consequent retention after the completion of exhaustive MD simulations. Top seven designed compounds were synthesized and evaluated for in-vitro anti-fungal property against Candida, which indicated that compounds 1.2c and 1.2f possess improved and comparable anti-fungal activity to N -(1,3-benzothiazole-2-yl)-2-(pyridine-3-ylformohydrazido) acetamide and Nystatin, respectively., Competing Interests: NOne, (© 2022 Published by Elsevier B.V.)

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. Around 202 SNPs in the ALR2 gene were reported in the dbSNP database. Out of these, eighteen SNPs that are responsible for point mutations in the regulatory sites of ALR2 enzyme were identified and considered for the study. Identified SNPs were then categorized as stabilizing or destabilizing using various in silico tools and webservers. The resulting mutational constructs of ALR2 were further probed for their influence on the binding affinities and binding modes with well-known ALR2 inhibitors using structure-based analyses. This study identified three destabilizing SNPs, i.e., rs779176563 (C298S), rs1392886142 (G16A), and rs1407261115 (A245T), that lead to the compromised response to most of the ALR2 inhibitors which are in clinical trials. On the other hand, treatment with these ALR2 inhibitors may benefit the population which carries missense SNPs rs748119899, rs1402962430, and rs1467939858 that code for W219S, Q183V, and S214A, respectively. Overall findings of the study suggest that one SNP in the inhibitor site and two SNPs in the co-factor site of ALR2 may be responsible for the low efficacy and unsuccessful journey of ALR2 inhibitors in the clinical trials., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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. ADME and PAINS filters were applied to provide drug-likeness and to remove toxicophores from the screened hits. The pharmacophoric features of 4-hydroxy-2-nonenal (HNE), a well-known substrate of ALR1, were also explored to identify selective ALR2 inhibitors. The structure-based analysis was then adopted to find out the molecules showing interactions with ALR2 which are crucial for their therapeutic activity. These interaction patterns and binding modes were compared with that of epalrestat. Molecular dynamics (MD) analysis was also carried out to get more insight into the interactions of screened hits in the catalytic domain of ALR2. Additionally, the top hits were docked and simulated with aldehyde reductase (ALR1) to determine their selectivity for ALR2 over ALR1. Overall, five hits including STOCKIN-44771, STOCKIN-46041, STOCKIN-59369, STOCKIN-69620 and STOCKIN-88220 were found to possess a good therapeutic profile in terms of key interactions, binding energies and drug-likeness. Two hits, STOCKIN-46041 and STOCKIN-59369, were identified as the most selective ALR2 inhibitors when assessed their selectivity profile.Communicated by Ramaswamy H. Sarma.

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. Multiple components are involved in these pathological pathways. Out of all, Von Willebrand Factor (VWF) is one of the primary components of coagulation pathway and also a mediator of vascular inflammation that plays an important role in thrombo-inflammation that further leads to acute respiratory distress syndrome (ARDS). The thrombo-inflammatory co-morbidities such as hyper-coagulation, thrombosis, ARDS etc. have become the major cause of mortality in the patients of COVID-19 admitted to the ICU. Thus, VWF can be explored as a potential target to manage COVID-19 associated co-morbidities. Supporting this hypothesis, there are literature reports which disclose previous attempts to target VWF for the management of thrombo-inflammation in other pathological conditions. The current report summarizes emerging insights into the pathophysiology, mechanism(s), diagnosis, management and foundations for research on this less explored clinically relevant glycoprotein as coagulation biomarker in COVID-19., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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. Literature reports suggest that diversely substituted benzimidazoles possess distinct pharmacological profiles with multi-targeting potential, thereby, an indispensable anchor for the development of novel therapeutic agents against complex diseases such as cancer, malaria, inflammatory disorders, microbial diseases, hypertension, etc. Thus, lots of efforts have been diverted towards exploring the therapeutic potential of benzimidazoles. Despite great efforts made by the research community, still, some multi-factorial diseases continue to progress due to their complex pathophysiology. Under these sets of circumstances, there is a need to explore this nucleus for hybrid designing with multi-targeting potential against complex diseases. Benzimidazole-based hybrids have been reported to treat multifactorial diseases, making it a scaffold of interest for various pharmaceutical companies and research groups. In this write-up, we shed light on the recent pharmacological profiles, various designing strategies, and structure-activity relationships (SAR) of different benzimidazole-based hybrids., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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. Docking analysis of the selected compounds was carried out within the active site of wild-type (WT) ROS-1 as well as Gly2032Arg mutant ROS-1 protein, which confirmed the retention of conserved interaction between selected molecules and hinge region amino acids Glu2027 and Met2029. Docking was followed by molecular dynamics simulations for the stability of the complexes and calculation of the MM-GBSA score for binding affinity. Finally, compounds were synthesized and the anti-proliferative potential of compounds was evaluated using the A549 cell line. Compounds 3a and 3b presented significant GI 50 values between 23.0 and 25.4 μM, among all the tested compounds.

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). ADMET analysis of prodrugs was then carried out to assess the drug-likeness. On the basis of in-silico results, the best five prodrugs were synthesized and further evaluated for their neuroprotective and nephroprotective potential in high-fat diet-streptozotocin (HFD-STZ) induced diabetes in rat model. Clinically relevant molecular manifestations of diabetic complications (DC) including aldose reductase (ALR2) activity and oxidative stress markers such as reduced glutathione (GSH), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) were determined in blood plasma as well as tissues of the brain and kidneys. The histopathological examination of these organs was also carried out to see the improvement in structural deformities caused due to neuropathy and nephropathy. Finally, in-vivo pharmacokinetic study was performed for the best two prodrugs to assess the improvement in biopharmaceutical attributes of parent drugs. Overall, EP-G-MFA and EP-MFA have significantly reduced the hyperglycemia-induced ALR2 activity, levels of oxidative stress markers, and manifested about a two-fold increase in the biological half-life (T 1/2 ) of parent drugs. The overall findings of this study suggest that methyl ferulate conjugated prodrugs of epalrestat may be considered as potential protective agents in diabetic neuropathy and nephropathy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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. To puzzle out this issue, several strategies inclusive of analog designing, prodrug designing, and inhibitor designing have been forged. On that front, the implementation of computational tools can be considered a fascinating approach to address the problem of chemoresistance. Various research groups have adopted different molecular modeling tools for the investigation of DMEs mediated toxicity problems. However, the utilization of these in-silico tools in maneuvering the DME mediated chemoresistance is least considered and yet to be explored. These tools can be employed in the designing of such chemotherapeutic agents that are devoid of the resistance problem. The current review canvasses various molecular modeling approaches that can be implemented to address this issue. Special focus was laid on the development of specific inhibitors of DMEs. Additionally, the strategies to bypass the DMEs mediated drug metabolism were also contemplated in this report that includes analogs and pro-drugs designing. Different strategies discussed in the review will be beneficial in designing novel chemotherapeutic agents that depreciate the resistance problem.

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., Introduction: The aim of this research was to perform phytochemical screening, and study cytotoxicity and anti-inflammatory activities to understand the potential of leaves of Lawsonia inermis of Indian origin to provide a way forward for therapeutic use in medicine., Methods: We assessed the phytochemical profile for the presence of phytoconstituents (alkaloids, carbohydrates, glycosides, steroids, flavonoids, saponins, tannins, proteins/amino acids and gums/mucilage) in various extracts of the plant leaves. The extracts were further purified by column chromatography for the isolation of plant constituents and monitored by TLC, analyzed by Fourier transform infrared FT-IR spectroscopy, H1NMR, and GC-MS analysis. Fractions were assessed for cytotoxicity and anti-inflammatory properties at various concentrations. We assessed the anti-inflammatory activity by nitric oxide production in various leaf extracts determined by Griess assay., Results: All the spectral results suggest that the compounds from the extract contain an aromatic nucleus and OH group along with the methoxy group, allyl as well as vinyl group. Fractions of chloroform/methanolic (7:3) leaf extract of Lawsonia inermis confirmed the presence of the two constituents i.e. fraxetin and 1(3H)-isobenzofuranone. We observed a significant difference in cytotoxicity at higher concentrations in methanol and chloroform: methanol (8:2) leaf extracts (p>0.05), we could not find any significant differences amongst other leaf extracts at different concentrations. Some leaf extracts have potential cytotoxic activity on Vero cells. Reducing the chloroform concentration during extraction decreases the cytotoxic effect on cells. Nitric oxide levels decreased from 1000 μg/ml concentration to lower concentrations with varying degrees. Overall the highest nitric oxide production by CHCl 3 (70%)/ MeOH (30%) was observed amongst various fractions at different concentrations., Conclusion: Phytochemical screening and the study of cytotoxicity and anti-inflammatory activities highlight the potential of leaves of the plant to provide a way further for their use in medicine. Fraxetin 1(3H) and isobenzofuranone structures were confirmed in fractions of CHCl 3 (70%)/ MeOH (30%) extract as potent constituents. Some leaf extracts have potential cytotoxic activity on Vero cells. Reducing the chloroform concentration during extraction, it decreases the cytotoxic effect on cells. The cytotoxicity studies indicate the presence of cytotoxic compounds in some of these extracts, warranting research for the fabrication of suitable formulations comprising these constituents to reduce dose/toxicity for beneficial effects of the plant components., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

EZH2 is a classic histone methyltransferase that causes the trimethylation of H3K27 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 EZH2 gene in determining the structure-function relationship towards breast cancer susceptibility. For this purpose the EZH2 SNPs (rs41277434A>C and rs201135441C>T (A490T)) were computationally explored and further the prediction outcomes were validated by performing population-based association and pharmacogenetic study in north Indian region of Punjab. The results of the present analysis provided the novel insight of rs201135441C>T (A490T) mutation, that A>T change i.e. nonpolar amino acid to polar amino acid stabilizes the enzyme-substrate ( EZH2 -Histone) complex which in turn promotes trimethylation over histone 3 (H3) at lysine residue 27 ( H3K27me3 ) and this might be leading to the methylation of the promoter region of various cancer preventive genes, hence may increase the risk of breast cancer susceptibility. Further the association based study of SNP rs201135441C>T (A490T) support the in silico outcomes by revealing that the T mutant allele of rs201135441 has significantly increased the risk of breast cancer susceptibility and also reduce the overall survival and progression free survival of ER+/tamoxifen treated breast cancer patients and triple negative breast cancer (TNBC) patients, respectively. To the best of our knowledge, this is the first study on EZH2 polymorphism with breast cancer. In conclusion, these findings suggest that these variations in the EZH2 gene may have strong clinical significance as they can be targeted for prognosis, prevention and in drug development.

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. The cytokine storm attracts many inflammatory cells that infiltrate into the lung tissues and ultimately cause immune damage. In addition to the dysregulation of the immune system, dysfunction of the renin-angiotensin system (RAS) due to the downregulation of ACE2 is also associated with the mortality of COVID-19 patients. Both the mechanisms are directly or indirectly associated with cytokine storm that promotes vascular hyperpermeability, vascular edema leading to hypercoagulation and hence multiorgan damage. As of now, there is no specific treatment available for COVID-19, but scientists have purposed several treatment options including cytokine inhibitors, JAK inhibitors, immunomodulators, plasma therapy, etc. In this article, we have provided the detailed mechanism of occurrence of SARS-CoV-2 induced inflammatory storm and its connection with the pre-existing inflammatory conditions. Possible treatment options to cope up with the severe clinical manifestations of COVID-19 are also discussed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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. The small molecular inhibitors are reported to limit the interaction of SP with ACE2 and other proteases. Arbidol, a membrane fusion inhibitor approved for influenza virus is currently undergoing clinical trials against COVID-19. In this context, we report some analogues of arbidol designed by scaffold morphing and structure-based designing approaches with a superior therapeutic profile. The representative compounds A_BR4, A_BR9, A_BR18, A_BR22 and A_BR28 restricted the interaction of SARS-CoV-2 SP with ACE2 and host proteases furin and TMPRSS2. For 3CLPro, Compounds A_BR5, A_BR6, A_BR9 and A_BR18 exhibited high binding affinity, docking score and key residue interactions. Overall, A_BR18 and A_BR28 demonstrated multi-targeting potential against all the targets. Among these top-scoring molecules A_BR9, A_BR18, A_BR22 and A_BR28 were predicted to confer favorable ADME properties., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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. Several ALR2 inhibitors have been reported, but none of them could reach US FDA approval. One of the main reasons is their poor selectivity over ALR1, which leads to the toxicity. The current review underlines the molecular connectivity of ALR2 with DC and comparative analysis of the catalytic domains of ALR2 and ALR1, to better understand the selectivity issues. This report also discusses the key features required for ALR2 inhibition and to limit toxicity due to off-target activity.

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. United States (US), Australian and European authorities related to Therapeutic Goods Administration (TGA) implemented the requirements to carry the "Black box" warning on the labels of COX-2 drugs highlighting the risks of serious cardiovascular events. These facts encouraged the researchers to explore them well and find out the biochemical basis behind the cardiotoxicity. From the last few decades, the molecular mechanisms behind the coxibs have regained the attention, especially the specific structural features of the selective COX-2 inhibitors that are associated with cardiotoxicity. This review discusses the key structural features of the selective COX-2 inhibitors and underlying mechanisms that are responsible for the cardiotoxicity. This report also unfolds different strategies that have been reported in the last 10 years to combat the problem of selective COX-2 inhibitors mediated cardiotoxicity., Competing Interests: Declaration of competing interest There is no potential conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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. Thus, in this study, dual inhibitors of ALR2 and SDH were identified using pharmacophore-based virtual screening. For this purpose, the pharmacophore model for SDH (model ID: AAADH.343) was generated and validated. For screening against ALR2, the pharmacophore model (model ID: AADRR.1109) which was previously reported by our group was applied. Initially, flavones reported by our research group were screened by those two pharmacophore models to obtain hits with an optimum affinity for the catalytic domain of both ALR2 and SDH. Inhibitory potential of identified hits for ALR2 and SDH were then experimentally determined using enzymatic assays reported in the literature. Additional focus was laid on the selectivity of the designed molecules towards ALR2 over ALR1, thus evaluation against ALR1 was also performed. Overall, four molecules FLV-2, FLV-11, FLV-12, and FLV-15 were found to possess significant dual inhibitory activity against ALR2 and SDH, with selectivity over ALR1. Among them, FLV-2 displayed significant dual inhibitory potential with an IC 50 value of 0.689 ± 0.018 µM and 0.174 ± 0.003 µM against ALR2 and SDH respectively with a selectivity index of 52.902 to ALR2 over ALR1., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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. Additionally, Verloop'ssterimol parameters (B1-B5, L) were calculated in order to investigate the steric constraint of prodrugs to the catalytic sites of hCES1 and hCES2 enzymes. Our results indicated that, among these prodrugs, EP-D4, EP-E13, EP-F5, and EP-F14 are best substrates for hCES1 while EP-G3 and EP-G15 are potential substrates for hCES2. On the other hand, EP-D19 serves as good substrates for both enzymes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The triazolopyrimidine scaffold represents one of the privileged structure in chemistry, and there has been an increase in number of studies utilizing this scaffold and its derivatives. Optimization of synthetic protocols such as aza-Wittig reaction, [3 + 2] cycloaddition reaction along with previous methods including condensation with 1,3-dicarbonyl substrates and oxidation of aminopyrimidine Schiff bases have been performed to obtain desired triazolopyrimidines. The triazolopyrimidine ring has been extensively used as a template in medicinal chemistry for its diverse pharmacological properties. Several medicinally active molecules possessing triazolopyrimidine scaffold, either fused or coupled with other heterocycles, have been reported in the literature, highlighting the significance of this nucleus. Interestingly, the unique triazolopyrimidine scaffold also exhibits an impressive potential as a ligand for the synthesis of several metal complexes with significant biological potential. Literature provides enough evidence of exhaustive exploration of this scaffold as a ligand for the chelates of platinum, ruthenium and other metals. This review aims to be a comprehensive and general summary of the different triazolopyrimidine syntheses, their use as ligands for the synthesis and development of metal complexes as medicinal agents and their main biological activities., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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). Therefore, this review emphasizes on pharmacokinetic resistance specifically the DMEs associated chemoresistance, in which drug molecule is rapidly metabolized by DMEs resulting in diminished potential of anti-cancer drugs. The current review will be covering DMEs that are associated with chemoresistance such as ALDH1A1, GST-π, DPD, CYP1B1 and so forth. Although several strategies have been developed to solve this problem such as prodrug designing, analog designing, DMEs inhibitors designing and development of specific pharmaceutical formulations but the inhibition of DMEs is still not considered significantly. Considering the significance of DMEs in chemoresistance, this review shed light on the mechanism of DMEs associated resistance at molecular level, their reported inhibitors that can be used as an adjuvant therapy and strategies (like prodrug designing, analog designing etc.) used so far to combat this problem.

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. Nowadays, this strategy is also being adopted against diabetes and its complications. Under hyperglycemic conditions, many pathways get activated which are responsible for the progression of diabetes-associated secondary complications viz. retinopathy, neuropathy, and nephropathy. The enzymes involved in the progression of these complications can be mimicked for their effective management. For an instance, Aldose Reductase (ALR2), a rate-limiting enzyme of the polyol pathway (downstream pathway) which gets over-activated under hyperglycemic condition is reported to be mimicked by using polymers which are having same functionalities in their structure. This review aims at critically appraising reports in which target mimicking bio-inspired formulations have been envisaged against diabetes and its complications. The information summarized in this review will provide an idea about the bio-sensing approaches utilized to manage blood glucose level and the utility of bio-inspired polymers for the management of diabetic complications (DC). Such type of information may be beneficial to pharmaceutical companies and academia for better development of targeted drug delivery systems with sustained-release property against these diseased conditions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Diabetic complications follow multiple pathophysiological pathways involving aldose reductase (ALR2)-mediated polyol pathway, advanced glycation end products (AGEs) and reactive oxygen species formation. Literature suggests ALR2 inhibitors such as epalrestat to possess significant potential in retinopathy and neuropathy. Thus, in this study, multiple pathophysiology directed molecules targeting ALR2, AGEs and free radicals formation were designed using in silico techniques. Initially, database was screened via in silico tools to obtain hits with affinity for the catalytic domain of ALR2. Additional focus was laid on the presence of structural attributes responsible for AGE's inhibitory and anti-oxidant potential. Out of obtained hits, 2-benzoxazolinone scaffold was selected and ten derivatives were synthesized accordingly. Finally, the synthesized molecules were evaluated for their ALR2 and AGEs inhibitory activities along with free radical scavenging potency., (© 2018 John Wiley & Sons A/S.)

Complex diseases comprises of highly complicated etiology resulting in limited applicability of conventional targeted therapies. Consequently, conventional medicinal compounds suffer major failure when used for such disease conditions. Additionally, development of multidrug resistance (MDR), adverse drug reactions and clinical specificity of single targeted drug therapy has increased thrust for novel drug therapy. In this rapidly evolving era, natural product-based discovery of hybrid molecules or multi-targeted drug therapies have shown promising results and are trending now a days. Historically, nature has blessed human with different sources viz. plant, animal, microbial, marine and ethnopharmaceutical sources which has given a wide variety of medicinally active compounds. These compounds from natural origin are always choice of interest of medicinal chemists because of their minimum side effects. Hybrid molecules synthesized by fusing or conjugating different active molecules obtained from these sources are reported to synergistically block different pathways which contribute in the pathogenesis of complex diseases. This review strives to encompass all natural product-derived hybrid molecules which act as multi-targeting agents striking various targets involved in different pathways of complex diseased conditions reported in literature., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Nitrogen and sulphur based heterocyclic molecules have gained significant attention owing to their broad spectrum pharmacological profiles. Thiazine is one of such promising scaffolds which has been widely utilized in the synthesis of compounds that possess interesting biological profile including anti-proliferative, anti-bacterial, antipsychotic, analgesic, anti-inflammatory, antifungal and antiviral activities. The current review focuses on the chemistry of thiazine and its derivatives along with potential pharmacological activities reported for these in scientific literature. Multifaceted pharmacological profile of thiazine derivatives provides new aspects for the design of superior medicinally active agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Trypanosoma evansi, the causative agent of surra, is pathogenic to a wide variety of wild and domestic animals, including equines, camels, goats, sheep, cattle, buffaloes, pigs, dogs, tigers, elephants etc. The infection is mainly restricted to animals but ability to infect human beings has also been reported due to the lack of efficient apolipoprotein L 1. The parasite is mechanically transmitted by blood-sucking flies such as Tabanus and Stomoxys species. The disease has a major economic impact in tropical countries. The control of trypanosomosis may be aimed either at the fly or against the parasite. Due to difficulties in large scale fly control, trypanocides have been widely used to control the disease. However, current chemotherapeutic agents are limited in number and usually associated with severe side effects. Moreover, current therapeutic agents are far from ideal. The emergence of drug resistant trypanosomes results in failure of prophylaxis and treatment of the disease. Retrospective and prospective studies on drug and delivery against T. evansi will provide an overview of the chemotherapeutic and prophylactic measures in vogue and suggest future strategies for combating this neglected disease. In this perspective, we have reviewed the currently used drugs available for prophylaxis and therapy, their mechanism of action and associated limitations. The options available for prophylaxis and therapy along with potential new molecules/therapeutic agents and novel approaches for delivery of the drugs to enhance their therapeutic value are presented in this review.