Pyrazolo[3,4-d]pyrimidines as inhibitor of anti-coagulation and inflammation activities of phospholipase A 2 : insight from molecular docking studies

Yadava, Umesh; Singh, Maheshwer; Roychoudhury, Mihir

doi:10.1007/s10867-013-9299-7

Cited by 35 publications

(19 citation statements)

References 61 publications

(58 reference statements)

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“…The G-score takes into account a number of parameters like hydrogen bonds, hydrophobic contacts, Coulombic, van der Waals, polar interactions in the binding site, metal binding terms and energy penalties for freezing rotatable bonds and buried polar groups. The Extra-Precision (XP) docking protocol of Glide includes protein-ligand structural motifs leading to enhanced binding affinity, in addition to unique water desolvation energy terms [14,15].…”

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confidence: 99%

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Stabilization of Microtubules by Taxane Diterpenoids: Insight from Docking and MD simulations

2014

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Microtubules are formed from the molecules of tubulin, whose dynamics is important for many functions in a cell, the most dramatic of which is mitosis. Taxol is known to interact within a specific site on tubulin and also believed to block cell-cycle progression during mitosis by binding to and stabilizing microtubules. Along with the tremendous potential that taxol has shown as an anticancer drug, clinical problems exist with solubility, toxicity, and development of drug resistance. The crystal structure of taxane diterpenoids, namely, 10, 13-deacetyl-abeo-baccatin-IV (I), 5-acetyl-2-deacetoxydecinnamoyl-taxinine-0.29hydrate (II), 7, 9-dideacetyltaxayuntin (III), and Taxawallin-K (IV), are very similar to the taxol molecule. Considerable attention has been given to such molecules whose archetype is taxol but do not posses long aliphatic chains, to be developed as a substitute for taxol with fewer side effects. In the present work, the molecular docking of these taxane diterpenoids has been carried out with the tubulin alpha-beta dimer (1TUB) and refined microtubule structure (1JFF) using Glide-XP, in order to assess the potential of tubulin binding of these cytotoxic agents. Results show that all the ligands dock into the classical taxol binding site of tubulin. Taxol shows the best binding capabilities. On the basis of docking energy and interactions, apart from taxol, molecule II has a better tendency of binding with 1TUB while molecule I shows better binding capability with bovine tubulin 1JFF. To validate the binding capabilities, molecular dynamics (MD) simulations of the best docked complexes of ligands with 1JFF have been carried out for 15.0 ns using DESMOND. Average RMSD variations and time line study of interactions and contacts indicate that these complexes remain stable during the course of the dynamics. However, taxol and molecule II prevail over other taxoids.

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confidence: 99%

“…Further, whole systems were minimized to an RMSD of 0.30 Å. Other parameters were taken as reported in our earlier paper [15]. β-tubulin lacks 18 residues in 1TUB, while no missing residue was observed in the β-tubulin of 1JFF.…”

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confidence: 99%

Stabilization of Microtubules by Taxane Diterpenoids: Insight from Docking and MD simulations

2014

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“…1 H NMR and 13 C NMR spectra were measured on a Bruker 400 MHz spectrometer (Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt) in D 2 O, DMSO-d 6 with TMS as the internal standard, where J (coupling constant) values were estimated in Hertz (Hz). Mass spectra were run on Hewlett Packard 5988 spectrometer.…”

Section: Chemistrymentioning

confidence: 99%

“…Unfortunately, some cardiovascular side effects such as myocardial infarction and increased incidences of high blood pressure caused by the highly selective COX-2 inhibitors led to the withdrawal of rofecoxib and valdecoxib from the market 10,11 . Pyrazolo [3,4-d]pyrimidine represents one of the most frequently found scaffold in a wide variety of anti-inflammatory agents 12,13 . The 5-benzamido-1H-pyrazolo [3,4-d]pyrimidin-4-one derivative (7) showed superior inhibitory profile against COX-2 when compared to that of reference standards N-[2-(cyclohexyloxy) 4-nitrophenyl]methane sulfonamide (NS398) and indomethacin 14 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of new 1-phenylpyrazolo[3,4-d]pyrimidine derivatives

Bakr

Azouz

Abdellatif

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A new group of 1-phenylpyrazolo [3,4-d]pyrimidine derivatives 14a-d-21 were synthesized from 2-(6-methyl-1-phenyl-1H-pyrazolo [3,4-d]pyrimidin-4-yloxy)acetohydrazide (12). All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, antiinflammatory activity and ulcerogenic liability. All the target compounds were more potential in inhibiting COX-2 than COX-1. Compounds having pyrazolyl moiety in a hybrid structure with pyrazolo[3,4-d]pyrimidine scaffold (14a-d, 16 and 17) showed higher edema inhibition percentage activities (34-68%) and the 5-aminopyrazole derivative (14c, ED 50 ¼ 87.9 mmol/kg) was the most potent one4celecoxib (ED 50 ¼ 91.9 mmol/kg). While, the in vivo potent compounds (14a-d, 16, 17 and 21) caused variable ulceration effect (ulcer index ¼ 0.33-4.0) comparable to that of celecoxib (ulcer index ¼ 0.33), the pyrazol-3-one derivative (16) and the acetohydrazide (21) were the least ulcerogenic derivatives showing the same ulcerogenic potential of celecoxib.

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“…Pyrazolo [3,4-d]pyrimidine molecules comprise a class of physically occurring fused uracils that exhibit assorted biological activities such as potential anti-inflammatory agents (Bekhit and Abdel-Azeim, 2004), adenosine receptors (Davies et al, 1984), anticoagulation inhibitor (Yadava et al, 2013), xanthine oxidase inhibitor (Elion et al, 1963), antiproliferative and proapoptotic agents in many tumor types (Schenone et al, 2010). They are also useful in the treatment of human cancers underneath oncogenic activation of RET (Carlomagno et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Pyrazolo[3,4-d]pyrimidines as the inhibitors of mycobacterial β-oxidation trifunctional enzyme

2015

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Tuberculosis, one of the oldest known human diseases, is still one of the major causes of mortality. Mycobacterium, a genus of Actinobacteria, is responsible for tuberculosis (Mycobacterium tuberculosis) and leprosy (Mycobacterium leprae). Because of producing high toxicity and resistance of existing drugs, the antitubercular drugs with less toxicity, potential activity and safer therapeutic profiles is an urgent need. Pyrazolo[3,4-d]pyrimidine compounds show various pharmacological activities including antitubercular. Molecular docking studies of eight pyrazolo[3,4-d]pyrimidine derivatives have been carried out with the mycobacterial b-oxidation trifunctional enzyme (mtTFE) using Autodock and Glide docking protocols. The docking results demonstrate good binding capabilities of these molecules with mtTFE. Molecular dynamics simulations of the best docked complexes of the compounds demonstrating better binding affinities and satisfactory ADME properties have been carried out using DESMOND for 10.0 ns duration. The average RMSD variation and simulation interaction study indicate that the complexes remain stable during the course of dynamics. However, molecules 6 and 7 exhibit better stability than other molecules and are the suitable candidates to be carried forward as a potential lead in the discovery of drugs to contest tuberculosis.

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Pyrazolo[3,4-d]pyrimidines as inhibitor of anti-coagulation and inflammation activities of phospholipase A 2 : insight from molecular docking studies

Cited by 35 publications

References 61 publications

Stabilization of Microtubules by Taxane Diterpenoids: Insight from Docking and MD simulations

Stabilization of Microtubules by Taxane Diterpenoids: Insight from Docking and MD simulations

Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of new 1-phenylpyrazolo[3,4-d]pyrimidine derivatives

Pyrazolo[3,4-d]pyrimidines as the inhibitors of mycobacterial β-oxidation trifunctional enzyme

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