Pharmacophore and docking-based hierarchical virtual screening for the designing of aldose reductase inhibitors: synthesis and biological evaluation

Vyas, Bhawna; Singh, Manjinder; Kaur, Maninder; Silakari, Om; Bahia, Malkeet Singh; Singh, Baldev

doi:10.1007/s00044-016-1510-5

Cited by 17 publications

(10 citation statements)

References 53 publications

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“…The other known C(6)-oxygenated flavonoids were identified as 6,3',4'-trihydroxy-3,5,7-trimethoxyflavone (3), [14] axillarin (4), [15] spinacetin (5), [16] patuletin (6), [17] nepetin (7), [18] hispidulin (8), [19] and 2R,3R-dihydroquercetagetin (9). [20] Previous studies show that C(6)oxygenated derivatives are a common constituent in the chemical profile of flavonoid aglycones occurring in the genus Ambrosia.…”

Section: Resultsmentioning

confidence: 99%

A New Lignan and C(6)‐Oxygenated Flavonoids from the Inflorescence of Ambrosia artemisiifolia

Zeng

Cheng

Lai

et al. 2022

Chemistry & Biodiversity

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A new lignan (4,4',5'-trihydroxy-5,3'-dimethoxy-3-O-9',2-(7'R)-lignan, 1) and eight C(6)-oxygenated flavonoids (2 -9), including a newly identified flavonoid (7,3',4'-trihydroxy-3,5,6-trimethoxyflavone, 2), were isolated from the inflorescence of Ambrosia artemisiifolia L. The structures of these isolates were determined using extensive spectroscopic analyses and comparison with data previously reported in the literature. The absolute configuration of compound 1 was established using electronic circular dichroism (ECD) spectrum. All the flavonoids (2 -9) showed inhibitory effects on LPS-induced NO production in RAW264.7 cells, with the inhibition rate ranging from 24.51 % to 69.82 % at 50 μM. The in vitro cytotoxicity study showed that compounds 3-8 have a 60 % inhibition rate against SMMC-7721 at a concentration of 40 μM, while compounds 5 and 8 also exhibited inhibitory activity against HL-60 at 40 μM with the inhibition rate of 83.36 % and 52.01 %, respectively.

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Section: Resultsmentioning

confidence: 99%

A New Lignan and C(6)‐Oxygenated Flavonoids from the Inflorescence of Ambrosia artemisiifolia

Zeng

Cheng

Lai

et al. 2022

Chemistry & Biodiversity

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“…Thus, the study indicates that His 802, Asp934, His802, Leu943, Arg681, Phe812 were the key amino acids residues in the active site involved in hydrogen bond interactions of HDAC4 with selected molecules (SEI and ACI) which aligns with recent studies on HDACi binding pattern (Ragno et al, 2006). Our pharmacophore model ADDRR.20 was also in alignment with the previous developed models toward histone de-acetylases (HDAC's) with known hydroxamic acids and cyclic peptides having four pharmacophore features i.e., one hydrogen bond acceptor, one hydrophobic group, and two aromatic rings (Vyas et al, 2016) and also with known hydroxamic acids, benzamides, and biphenyl derivatives on HDAC8 (Vadivelan et al, 2008) having three pharmacophore features i.e., hydrogen bond acceptors, hydrogen bond donors, and hydrophobic aromatic ring. Thus, our developed pharmacophore model with known hydroxamide derivatives toward HDAC4 having five pharmacophore features i.e., one hydrogen acceptor (HBA), two hydrogen donor (HBD), and two aromatic rings (RA) correlates with the previous studies (Thangapandian et al, 2010a).…”

Section: Discussionmentioning

confidence: 95%

Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

et al. 2017

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Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r2) value of 0.6774, cross-validated correlation coefficient (q2) of 0.6157 and co-relation coefficient for external test set (pred_r2) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of −10.097 and −9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free energy binding calculations using the g_mmpbsa technique. Prediction of inhibitory activities of the two lead compounds SEI (7.53) and ACI (6.84) using the 3D-QSAR model reaffirmed their inhibitory characteristics as potential anti-ataxia compounds.

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“…Previously reported Ligand‐based pharmacophore models for ALR2, generated using Phase module of Schrödinger was employed to screen an in‐house small molecule database. This screening yielded 2‐benzoxazolinone derivatives as hits, which were then subjected to docking analysis using co‐crystallized 3‐D structure of ALR2 followed by molecular dynamic simulations and calculation of MM‐GBSA score (binding energies).…”

Section: Resultsmentioning

confidence: 99%

Identification of 2‐benzoxazolinone derivatives as lead against molecular targets of diabetic complications

et al. 2018

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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.

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Pharmacophore and docking-based hierarchical virtual screening for the designing of aldose reductase inhibitors: synthesis and biological evaluation

Cited by 17 publications

References 53 publications

A New Lignan and C(6)‐Oxygenated Flavonoids from the Inflorescence of Ambrosia artemisiifolia

A New Lignan and C(6)‐Oxygenated Flavonoids from the Inflorescence of Ambrosia artemisiifolia

Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

Identification of 2‐benzoxazolinone derivatives as lead against molecular targets of diabetic complications

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