Inhibitory effect of Nifedipine on aldose reductase delays cataract progression.

Aldose reductase (ALR2) is a rate-limiting component of the polyol pathway, which is essential for the NADPH-mediated conversion from glucose to sorbitol. ALR2 dysregulation has been linked to α-crystallin aggregation, increased oxidative stress, and calcium inflow, all of which contribute to a diabetic cataract. Given its crucial role in occular pathologies, ALR2 has emerged as a promising target to treat oxidative stress and hyperglycaemic condition which form the underlying cause of diabetic cataracts. However, several of them had issues with sensitivity and specificity to ALR2, despite being screened as effective ALR2 inhibitors from a wide range of structurally varied molecules. The current study investigates the inhibitory potential of Nifedipine, an analog of the dihydro nicotinamide class of compounds against ALR2 activity. The enzyme inhibition studies were supported by in vitro biomolecular interactions, molecular modeling approaches, and in vivo validation in diabetic rat models. Nifedipine demonstrated appreciable inhibitory potential with the purified recombinant hAR (human aldose reductase; with an IC50 value of 2.5 µM), which was further supported by Nifedipine-hAR binding affinity (Kd = 2.91 ± 1.87 × 10-4 M) by ITC and fluorescence quenching assays. In the in vivo models of STZ-induced diabetic rats, Nifedipine delayed the onset progression of cataracts by preserving the antioxidant enzyme activity (SOD, CAT, and GPX GSH, TBARS, and protein carbonyls) and was shown to retain the α-crystallin chaperone activity by reducing the calcium levels in the diabetic rat lens. In conclusion, our results demonstrate effective inhibition of ALR2 by Nifedipine, resulting in amelioration of diabetic cataract conditions by lowering oxidative and osmotic stress while retaining the chaperone activity of α-crystallins. The present study could be envisaged to improve the eye condition in older adults upon Nifedipine treatment.

An RNA-immunoprecipitation via CRISPR/dCas13 reveals an interaction between the SARS-CoV-2 5'UTR RNA and the process of human lipid metabolism.

We herein elucidate the function of SARS-CoV-2derived 5'UTR in the human cells. 5'UTR bound host cellular RNAs were immunoprecipitated by gRNA-dCas13 (targeting luciferase RNA fused to SARS-CoV-2 5'UTR) in HEK293T and A549 cells. The 5'UTR bound RNA extractions were predominantly enriched for regulating lipid metabolism. Overexpression of SARS-CoV-2 5'UTR RNA altered the expression of factors involved in the process of the human Mevalonate pathway. In addition, we found that HMG-CoA reductase inhibitors were shown to suppress SARS-CoV-2 5'UTR-mediated translation activities. In conclusion, we deduce the array of host RNAs interacting with SARS-CoV-2 5'UTR that drives SARS-CoV-2 translation and influences host metabolic pathways.

Intrinsic activation of cardiosphere-derived cells enhances myocardial repair.

OBJECTIVE: Permanent loss of cardiomyocytes after myocardial infarction results in irreversible damage to cardiac function. The present study aims to enhance the cardiomyogenic efficiency of cardiosphere-derived cells (CDCs) to develop into large populations of cardiomyocytes by intrinsic activation of cardio-specific differentiation factors (Gata4, Mef2c, Nkx2-5, Hand2, and Tnnt2) by a CRISPR/dCas9 assisted transcriptional enhancement system. METHODS: Exhaustive screening was performed to identify the specific sequences in endogenous regulatory regions (enhancers and promoters) responsible for transcriptional activation of the target genes, via a CRISPR/dCas9 system fused with transcriptional activator VP64 (CRISPR-dCas9-VP64). In a rat model of acute myocardial infarction, we compared the regenerative potential and functional benefits of CDCs with or without transcriptional activation. RESULTS: We identified a panel of specific CRISPR RNA targeting the enhancers and promoters, which demonstrated significantly higher expression of differentiation factors of Gata4, Hand2, and Tnnt2. The group of CDCs with transcriptional activator VP64 (CDC with VP64) showed significant improvement in the left ventricular ejection fraction (61.9% vs 52.5% and 44.1% in the CDC without transcriptional activation group and control) and decreased scar area in the heart. CONCLUSIONS: We have identified endogenous regulatory regions responsible for an intrinsic activation of cardio-specific differentiation factors assisted via a CRISPR/dCas9 gene transcriptional system. The CRISPR/dCas9 system may provide an efficient and effective means of regulating Tnnt2 gene activation within stem cells. Subsequently, this system can be used to enhance transplanted CDCs differentiation potential within ischemic myocardia to better therapeutic outcomes of patients with ischemic heart disease.

Structure-based design of gRNA for Cas13.

Cas13 endonuclease activity depends on the RNA local secondary structure with strong preference for single-stranded (SS) regions. Hence, it becomes indispensable to identify the SS regions for effective Cas13 mediated RNA knockdown. We herein present rational gRNA design by integrating experimental structure-seq data and predicted structural models. Utilizing structure-seq data for XIST transcript, we observed that gRNAs targeting the SS regions significantly induce transcript knockdown and cleavage than those targeting double-stranded (DS) regions. Further, we identified the "central seed region" in the gRNA that upon targeting the SS regions efficiently facilitates Cas13 mediated cleavage. In our following pursuits, we considered the scenario wherein experimental structure-seq data is not available, hence we used SS18-SSX2 fusion transcript indicated in synovial sarcomas and computationally predicted its structure. We observed that gRNAs targeting the SS regions predicted from the structure, efficiently induced necrosis compared to gRNAs that target the DS regions. In conclusion, for the effective RNA knockdown, the Cas13 mediated targeting strategy presented herein emphasizes the designing of gRNAs specifically targeting SS regions by utilizing structural information. Further, this strategy, in turn, can be anticipated to narrow the search space for gRNA design (by exclusively targeting SS regions) especially when lncRNAs are the targets.

Impact of heavy rains of 2018 in western Japan: disaster-induced health outcomes among the population of Innoshima Island.

Southwestern Japan suffered its worst rains in 2018 causing floods and mudslides, claiming 225 lives and forcing millions for evacuations. Referred as "Heisei san-ju-nenshichi-gatsugou", the disaster was the result of incessant precipitation caused by the interaction of typhoon "Prapiroon" with the seasonal rain front "Baiu". The present epidemiological study aims to investigate disaster-induced health issues in 728 residents of Innoshima island in the Hiroshima Prefecture by comparing their clinical data in pre-disaster (2017) and disaster-hit (2018) years which was obtained from annual health screening. Comparison of data showed a significant increase in the urine protein concentration in victims following the disaster. Probing further into the household conditions, showed that a total of 59,844 households were affected with water outage during the heavy rains, which was accompanied by severe damage of sewerage pipelines with complete recovery process taking two weeks. This two weeks of the crisis forced victims to refrain from using restrooms which in turn led to infrequent urination, thereby explaining the increased urine protein concentration in victims following the disaster. The present study addresses the acute health implications caused by the water crisis and serves as a precautionary measure for disaster management council to provide enhanced aftercare services in victims in further events of natural disasters.

Molecular dynamic simulations reveal suboptimal binding of salbutamol in T164I variant of ß2 adrenergic receptor.

The natural variant C491T (rs1800088) in ADRB2 gene substitutes Threonine to Isoleucine at 164th position in ß2AR and results in receptor sequestration and altered binding of agonists. Present investigation pursues to identify the effect of T164I variation on function and structure of ß2AR through systematic computational approaches. The study, in addition, addresses altered binding of salbutamol in T164I variant through molecular dynamic simulations. Methods involving changes in free energy, solvent accessibility surface area, root mean square deviations and analysis of binding cavity revealed structural perturbations in receptor to incur upon T164I substitution. For comprehensive understanding of receptor upon substitution, OPLS force field aided molecular dynamic simulations were performed for 10 ns. Simulations revealed massive structural departure for T164I ß2AR variant from the native state along with considerably higher root mean square fluctuations of residues near the cavity. Affinity prediction by molecular docking showed two folds reduced affinity of salbutamol in T164I variant. To validate the credibility docking results, simulations for ligand-receptor complex were performed which demonstrated unstable salbutamol-T164I ß2AR complex formation. Further, analysis of interactions in course of simulations revealed reduced ligand-receptor interactions of salbutamol in T164I variant. Taken together, studies herein provide structural rationales for suboptimal binding of salbutamol in T164I variant through integrated molecular modeling approaches.

Association of CnB 5I/5D promoter gene polymorphism and serum calcineurin levels in early onset of coronary artery disease of south Indian cohort.

Calcineurin, a serine/threonine phosphatase is a calcium dependent protein which on activation triggers transcriptional up regulation of inflammatory genes associated with inflammation in the arteries and progressive formation of plaques in CAD. The present investigation is aimed to study the possible association of Calcineurin encoding gene PPP3R1 (CnB 5I/5D) polymorphism in correlation with serum levels of calcineurin in coronary artery disease (CAD). A total of 300 angiographically documented CAD patients and 300 age, gender ethnicity matched healthy controls were recruited for the study. Serum Calcineurin levels were estimated by enzyme-linked immunosorbent assay (ELISA) and genotypes were determined based on PCR-RFLP. The CnB 5I/5D variation was found to be significantly associated with CAD (p<0.03), correlated to elevated serum calcineurin levels encoded by (<0.01) 5I/5D allele authenticated by Insilco analysis. Multiple logistic regression analysis also confirmed these findings [adjusted OR for DD genotype was 3.19 (95% CI 1.40-7.24) and p=0.001]. The results suggest that 5-base pair deletion results in increased serum calcineurin levels and may trigger up regulation of calcineurin which mediates vascular inflammation and atherosclerosis in CAD.

A Virtual Screening Approach for the Identification of High Affinity Small Molecules Targeting BCR-ABL1 Inhibitors for the Treatment of Chronic Myeloid Leukemia.

CML originates due to reciprocal translocation in Philadelphia chromosome leading to the formation of fusion product BCR-ABL which constitutively activates tyrosine kinase signaling pathways eventually leading to abnormal proliferation of granulocytic cells. As a therapeutic strategy, BCR-ABL inhibitors have been clinically approved which terminates its phosphorylation activity and retards cancer progression. However, a number of patients develop resistance to inhibitors which demand for the discovery of new inhibitors. Given the drawbacks of present inhibitors, by high throughput virtual screening approaches, present study pursues to identify high affinity compounds targeting BCR-ABL1 anticipated to have safer pharmacological profiles. Five established BCR-ABL inhibitors formed the query compounds for identification of structurally similar compounds by Tanimoto coefficient based linear fingerprint search with a threshold of 95% against PubChemdatabase. Assisted by MolDock algorithm all compounds were docked against BCR-ABL protein in order to retrieve high affinity compounds. The parents and similars were further tested for their ADMET propertiesand bioactivity. Rebastinib formed higher affinity inhibitor than rest of the four established compound investigated in the study. Interestingly, Rebastinib similar compound with Pubchem ID: 67254402 was also shown to have highest affinity than other similars including the similars of respective five parents. In terms of ADMET properties Pubchem ID: 67254402 had appreciable ADMET profile and bioactivity. However, Rebastinib still stood as the best inhibitor in terms of binding affinity and ADMET properties than Pubchem ID: 67254402. Nevertheless, owing to the similar pharmacological properties with Rebastinib, Pubchem ID: 67254402 can be expected to form potential BCR-ABL inhibitor.

Helix-Coil Transition Signatures B-Raf V600E Mutation and Virtual Screening for Inhibitors Directed Against Mutant B-Raf.

BACKGROUND: Mutation in the B RAF at V600E has been well implicated in the carcinogenesis that makes it as an attractive therapeutictarget. In the present study, we sought to identify the basis of V600E mutation at functional and structural grounds. The study also endeavors in identification of small molecule as a potential candidate with considerable pharmacological profile than available BRAF inhibitors through computational approaches. METHODS: The functional effects of V600E mutation was predicted using SIFT and Polyphen servers. Protein structural alterations werepredicted using SDM server and RMSD calculations. Virtual screening was performed considering existing BRAF inhibitors viz., Vemurafenib, Sorafenib, Dabrfenib, Trametinibthat formed query compounds for shape similarity search by Tanimoto similarity indices with a threshold of 95%. Compound with high affinity as similar to query compound was retrieved and screened for its ADMET properties. RESULTS: The SNP was shown to be highly vulnerable to malfunction and have damaging effects. Mutated protein showed that the secondary structure was irregular and side chain hydrogen bonds were unsaturated. The superimposition of wild onto mutated V600E BRAF revealed helix-coil transition occurring wherein residues Val 502, Leu 505, Arg506, Lys 507 assumed coiled conformation in the mutated BRAF. Virtual screening led to identification of SCHEMBL298689 akin to Vemurafenib as high affinity B-Raf inhibitors; with least toxicity and optimal bioactivity. CONCLUSION: In the present investigation, we put forth the structural and functional basis of B RAF V600E mutation showing helix coil transitions. In addition identified high affinity compound targeting V600E B RAF through virtual screening.

Common SAR Derived from Linear and Non-linear QSAR Studies on AChE Inhibitors used in the Treatment of Alzheimer's Disease.

BACKGROUND: Deficits in cholinergic neurotransmission due to the degeneration of cholinergic neurons in the brain are believed to be one of the major causes of the memory impairments associated with AD. Targeting acetyl cholinesterase (AChE) surfaced as a potential therapeutic target in the treatment of Alzheimer's disease. The present study is pursued to develop quantitative structure activity relationship (QSAR) models to determine chemical descriptors responsible for AChE activity. METHODS: Two different sets of AChE inhibitors, dataset-I (30 compounds) and dataset-II (20 compounds) were investigated through MLR aided linear and SVM aided non-linear QSAR models. RESULTS: The obtained QSAR models were found statistically fit, stable and predictive on validation scales. These QSAR models were further investigated for their common structure-activity relationship in terms of overlapping molecular descriptors selection. Atomic mass weighted 3D Morse descriptors (MATS5m) and Radial Distribution Function (RDF045m) descriptors were found in common SAR for both the datasets. Electronegativity weighted (MATS5e, HATSe, and Mor17e) descriptors have also been identified in regulative roles towards endpoint values of dataset-I and dataset-II. CONCLUSION: The common SAR identified in these linear and non-linear QSAR models could be utilized to design novel inhibitors of AChE with improved biological activity.

Development of MLR and SVM Aided QSAR Models to Identify Common SAR of GABA Uptake Herbal Inhibitors used in the Treatment of Schizophrenia.

BACKGROUND: Alterations in GABAnergic system are implicated in the pathophysiology of schizophrenia. Available antipsychotics that target GABA receptor form a desirable therapeutic strategy in the treatment regimen of schizophrenia, unfortunately, suffer serious setback due to their prolonged side effects. The present investigation focuses on developing QSAR models from the biological activity of herbal compounds and their derivatives that promise to be alternative candidates to GABA uptake inhibitors. METHODS: Three sets of compounds were undertaken in the study to develop QSAR models. The first set consisted of nine compounds which included Magnolol, Honokiol and other GABA acting established compounds. The second set consisted of 16 derivatives of N-diarylalkenylpiperidinecarboxylic acid. The third QSAR dataset was made up of thirty two compounds which were Magnolol and Honokiol derivatives. Multiple linear regressions (MLR) and support vector machine (SVM) supervised quantitative structure-activity relationship (QSAR) models were developed to predict the biological activity of these three sets. The purpose of taking three QSAR sets of diverse chemical structures but identical in their GABA targeting and pharmacological action was to identify common chemical structure features responsible for structure-activity relationship (SAR). RESULTS: Linear and non-linear QSAR models confirmed that the three sets shared common structural descriptors derived from WHIM (Weighted Holistic Invariant Molecular descriptors), 3D-MoRSE and Eigenvalue classes. CONCLUSION: It was concluded that properties like electro negativity and polarizability play a crucial role in controlling the activity of herbal compounds against GABA receptor.

Design and synthesis of chiral 2H-chromene-N-imidazolo-amino acid conjugates as aldose reductase inhibitors.

Aldose reductase (ALR2) inhibitors provide a viable mode to fight against diabetic complications. ALR2 exhibit plasticity in the active site vicinities and possible shifts in the nearby two supporting alpha helices. Therefore, a novel series of amino acid conjugates of chromene-3-imidazoles (13-15) were designed and synthesized based on natural isoflavonoids. The compounds were identified on the basis of spectral (1H NMR, 13C NMR and MS) data and tested in vitro for ALR2 inhibitory activity with an IC50 value ranges from 0.031 ± 0.082 µM to 4.29 ± 0.55 µM. Our in silico and biochemical studies confirmed that 15e has the best inhibition activity among the synthesized compounds with a high selective index against the Aldehyde reductase (ALR1). Supplementation of 15e to STZ induced rats decreased the blood glucose levels and delayed the progression of cataract in a dose-dependent manner. The present study thus provides novel series of compounds with a promising inhibitor to prevent or delay the cataract progression.

Association of Beta 2 adrenergic receptor (Thr164Ile) polymorphism with Salbutamol refractoriness in severe asthmatics from Indian population.

BACKGROUND: Thr164Ile polymorphism in the ADRB2 gene encoding ß2 adrenergic receptor (ß2AR) has its functional consequence in declining ligand-receptor interactions and depressed coupling of ß2AR to adenylcyclase. In the present study, we sought to evaluate the possible association of Thr164Ile polymorphism with asthma susceptibility, pharmacogenetic response to Salbutamol and varying degrees of severity. METHODS: Three hundred and ninety eight clinically diagnosed patients and four hundred and fifty six healthy controls were enrolled in the study. Patients were classified into severity classes according to the Global Initiative for Asthma (GINA) guidelines. To assess bronchodilator response, spirometry was performed before and 15min after Salbutamol (200µg) delivery. Responders to Salbutamol were categorized if percentage reversibility was greater than or equal to 12% in them, while those showing reversibility <12% were classified as non-responders. Further, responding phenotypes were stratified into severity groups. Genotyping was carried out by ARMS-PCR technique. Statistical methods were applied to test the significance of the results. RESULTS: In the present study, polymorphism was not associated with disease susceptibility however; there was significant association with non-responding asthmatics. In case of severity subsets, the polymorphism was not associated with milder subtypes; although, notable association was observed with moderate and severe asthma subtypes. In addition, the polymorphism was significantly associated with non-responding patients with severe asthma. CONCLUSIONS: In south Indian population, the ADRB2 Thr164Ile polymorphism may not form susceptible variant to develop asthma, however, it can form a predictive maker for bronchodilator (Salbutamol) response in severe asthmatics.

Design, synthesis and computational evaluation of a novel intermediate salt of N-cyclohexyl-N-(cyclohexylcarbamoyl)-4-(trifluoromethyl) benzamide as potential potassium channel blocker in epileptic paroxysmal seizures.

The narrow therapeutic range and limited pharmacokinetics of available Antiepileptic drugs (AEDs) have raised serious concerns in the proper management of epilepsy. To overcome this, the present study attempts to identify a candidate molecule targeting voltage gated potassium channels anticipated to have superior pharmacological than existing potassium channel blockers. The compound was synthesized by reacting (S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4] benzodiazepine5,11(10H,11aH)-dione with 4-(Trifluoromethyl) benzoic acid (C8H5F3O2) in DMF and N,N'-dicyclohexylcarbodiimide (DCC) which lead to the formation of an intermediate salt of N-cyclohexyl-N-(cyclohexylcarbamoyl)-4-(trifluoromethyl)benzamide with a perfect crystalline structure. The structure of the compound was characterized by FTIR, 1H NMR and 13C NMR analysis. The crystal structure is confirmed by single crystal X-ray diffraction analysis. The Structure-Activity Relationship (SAR) studies revealed that substituent of fluoro or trifluoromethyl moiety into the compound had a great effect on the biological activity in comparison to clinically used drugs. Employing computational approaches the compound was further tested for its affinity against potassium protein structure by molecular docking in addition, bioactivity and ADMET properties were predicted through computer aided programs.

Common SAR Derived from Multiple QSAR Models on Vorinostat Derivatives Targeting HDACs in Tumor Treatment.

BACKGROUND: Dysregulation of HDACs has been associated with tumour development and therefore inhibiting HDAC's have surfaced as promising therapeutic strategy in malignancy. METHODS: Vorinostat analogues with different biological activities were investigated for underlying structure-activity relationship. RESULTS: Out of six activities and their multiple QSAR models, HDAC1 and HDAC8 produced statistically fit, stable and predictive linear (MLR) and non-linear (SVM) QSAR models. In case of HDAC1 activity as end point, linear (R2=0.8089, R2 CV=0.7343) and non-linear (R2=0.9801, R2 CV=0.8952) QSAR models turned reliable to investigate SAR. Similarly, HDAC8 activity based linear (R2=0.9454, R2 CV=0.9049) and non-linear (R2=0.9899, R2 CV=0.9232) QSAR models produced statistically improved and stable models. CONCLUSION: Molecular descriptors derived from 3-D Morse and Radial Distribution Function indices were found to be selective in all the models. These molecular descriptors which encode common SAR among Vorinostat derivatives were evaluated for their potent HDAC inhibition activity.

Identification of Small Molecule as a High Affinity β2 Agonist Promiscuously Targeting Wild and Mutated (Thr164Ile) β 2 Adrenergic Receptor in the Treatment of Bronchial Asthma.

BACKGROUND: A subset of asthmatics shows refractoriness to Salbutamol owing to ADRB2 gene C.T polymorphism (rs 1800888) that substitutes Thr to Ile at the position 164 in the ß2 adrenergic receptor leading to sub-optimal binding of Salbutamol. The present study aims to associate the Salbutamol (200 mcg) refractoriness with the polymorphism and select the best existing agonist with optimal binding affinity against wild and mutated receptor and further identify high affinity compound, irrespectively targeting wild and mutated receptor through virtual screening methods. METHODS: Responders to Salbutamol were categorized, if percentage reversibility was greater than or equal to 12% in them, while those showing reversibility less than 12% were non-responders. The genotyping for polymorphism was performed by ARMS PCR method. Established agonists with consistent binding affinity against wild and mutated receptors formed query compound to identify high affinity molecule from Phase database through 7 point pharmacophore based screening. RESULTS: Polymorphism was significantly associated with non-responders (p= < 0.05) demonstrating it as a major factor of Salbutamol refractoriness. Results from Glide Docking showed that Fenoterol had highest affinity for mutated receptor and stood as second best (after Salbutamol) high affinity agonist for wild receptor among the established ß2 agonists. Therefore Fenoterol formed a query molecule (7 point pharmacophore) in identification of high affinity compound for virtual screening process. CONCLUSION: Compound CACPD2011a-0001278239 identified through virtual screening against 4 million compounds in phase database was shown to irrespectively target both wild and mutated ß2 adrenergic receptor with high and consistent affinity which was par greater than established ß2agonists.

Virtual Screening Approaches in Identification of Bioactive Compounds Akin to Delphinidin as Potential HER2 Inhibitors for the Treatment of Breast Cancer.

Small molecule tyrosine kinase inhibitors targeting HER 2 receptors have emerged as an important therapeutic approach in inhibition of downstream proliferation and survival signals for the treatment of breast cancers. Recent drug discovery efforts have demonstrated that naturally occurring polyphenolic compounds like delphinidin have potential to inhibit proliferation and promote apoptosis of breast cancer cells by targeting HER2 receptors. While delphinidin may thus reduce tumour size, it is associated with serious side effects like dysphonia. Owing to the narrow therapeutic window of delphinidin, the present study aimed to identify high affinity compounds targeting HER2 with safer pharmacological profiles than delphinidin through virtual screening approaches. Delphinidin served as the query parent for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. The compounds retrieved were further subjected to Lipinski and Verber's filters to obtain drug like agents, then further filtered by diversity based screens with a cut off of 0.6. The compound with Pubchem ID: 91596862 was identified to have higher affinity than its parent. In addition it also proved to be non-toxic with a better ADMET profile and higher kinase activity. The compound identified in the study can be put to further in vitro drug testing to complement the present study.

Pharmacological Analysis of Vorinostat Analogues as Potential Anti-tumor Agents Targeting Human Histone Deacetylases: an Epigenetic Treatment Stratagem for Cancers.

Alteration of the acetylation status of chromatin and other non-histone proteins by HDAC inhibitors has evolved as an excellent epigenetic strategy in treatment of cancers. The present study was sought to identify compounds with positive pharmacological profiles targeting HDAC1. Analogues of Vorinostat synthesized by Cai et al, 2015 formed the test compounds for the present pharmacological evaluation. Hydroxamte analogue 6H showed superior pharmacological profile in comparison to all the compounds in the analogue dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify compounds with even better high affinity and pharmacological profile than 6H and Vorinostat, virtual screening was performed. A total of 83 compounds similar to Vorinostat and 154 compounds akin to analogue 6H were retrieved. SCHEMBL15675695 (PubCid: 15739209) and AKOS019005527 (PubCid: 80442147) similar to Vorinostat and 6H, were the best docked compounds among the virtually screened compounds. However, in spite of having good affinity, none of the virtually screened compounds had better affinity than that of 6H. In addition SCHEMBL15675695 was predicted to be a carcinogen while AKOS019005527 is Ames toxic. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report Vorinostat hydroxamate analogue 6H to be a potential candidate for HDAC inhibition in treatment of cancers through an epigenetic strategy.

Structural basis for the in vitro known acyl-depsipeptide 2 (ADEP2) inhibition to Clp 2 protease from Mycobacterium tuberculosis.

Inhibition of Mycobacterium tuberculosis Clp 2 protease has emerged as an attractive therapeutic option for treatment. Acyldepsipeptides (ADEPs) is known as an inhibitor for Clp 2 protease. Therefore, it is of interest to document its affinity, enzyme activity and ADME profiles. We report the predicted binding affinity of all known Clp 2 inhibitors like IDR-10001 and IDR-10011 against Clp2 protease using MolDock algorithm aided molecular docking. The predicted activity (using Molinspiration server) and ADMET properties (AdmetSAR server) were estimated for these compounds. This data suggest ADEP2 having improved binding features with Mtb Clp 2 having acceptable ADMET properties. This is in agreement with known in vitro data for ADEP2 inhibition with Mtb Clp 2 protease.

Virtual screening of RAGE inhibitors using molecular docking.

Advanced Glycation End products (AGEs) interaction with Receptor for AGEs (RAGE) activates downstream signaling and evokes inflammatory responses in vascular cells. Therefore, it is of interest to design a novel series of molecules with a library of 352 compounds based on natural Isoflavone and Argpyrimidine moities. The compounds screened against the optimized structure of RAGE (PDB code: 3CJJ) using MolDock aided with molecular docking algorithm. This exercise identified compound number 62 with appreciable ADME properties having no toxicity and pharmacophore features. Therefore, compound 62 identified as a RAGE inhibitor is proposed for further validation in the context of Diabetic Retinopathy (DR) and vascular complications.