High-throughput and<i>in silico</i>screenings in drug discovery

Phatak, Sharangdhar S.; Stephan, Clifford; Cavasotto, Claudio N.

doi:10.1517/17460440903190961

Cited by 85 publications

(74 citation statements)

References 99 publications

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“…This method was used as it was successful in picking up molecules with high binding affinity in Class A GPCR Melanin Concentrating Hormone receptor 1 (MCHR1) (Cavasotto et al, 2008). Further, this method was useful in predicting the experimental binding modes accurately, with results comparable to that of crystal structure (Phatak, Stephan, and Cavasotto, 2009;Phatak, Gatica and Cavasotto, 2010). It was also useful in rationalizing the binding of antagonists ( Ligand Docking with Energetics) with Prime optimization and refinement.…”

Section: Generation Of Agshms and Anshms Of Par2mentioning

confidence: 88%

Biased signaling: potential agonist and antagonist of PAR2

Kakarala¹,

Jamil²

2015

Journal of Biomolecular Structure and Dynamics

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Protease activated receptor 2 (PAR2) has emerged as one of the promising therapeutic targets to inhibit rapidly metastasizing breast cancer cells. However, its elusive molecular mechanism of activation and signaling has made it a difficult target for drug development. In this study, in silico methods were used to unfold PAR2 molecular mechanism of signaling based on the concept of GPCR receptor plasticity. Although, there are no conclusive evidences of the presence of specific endogenous ligands for PAR2, the efficacy of synthetic agonist and antagonist in PAR2 signaling has opened up the possibilities of ligand-mediated signaling. Furthermore, it has been proved that ligands specific for one GPCR can induce signaling in GPCRs belonging to other subfamilies. Therefore, the aim of this study was to identify potential agonists and antagonists from the GPCR ligand library (GLL), which may induce biased signaling in PAR2 using the concept of existence of multiple ligand-stabilized receptor conformations. The results of our in silico study suggest that PAR2 may show biased signaling mainly with agonists of serotonin type 1, β-adrenergic type 1,3 and antagonists of substance K (NK1), serotonin type 2, dopamine type 4, and thromboxane receptors. Further, this study also throws light on the putative ligand-specific conformations of PAR2. Thus, the results of this study provide structural insights to putative conformations of PAR2 and also gives initial clues to medicinal chemists for rational drug design targeting this challenging receptor.

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Section: Generation Of Agshms and Anshms Of Par2mentioning

confidence: 88%

Biased signaling: potential agonist and antagonist of PAR2

Kakarala¹,

Jamil²

2015

Journal of Biomolecular Structure and Dynamics

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“…About ten years ago, the advent of high-throughput screening (HTS) technology revolutionized the process of early drug development, enabling researchers to rapidly collect enormous amounts of data and explore compound libraries with unprecedented thoroughness (Phatak et al 2009). One of the fastest HTS systems is Lucio Freitas-Junior's at the Institute Pasteur in Korea: a 384-well cell-culture system that combines an automated confocal microscope with an image analyzer that can screen up to 30,000 compounds a week (Clayton 2010).…”

Section: Research Into Natural Productsmentioning

confidence: 99%

Natural products and Chagas’ disease: the action of triterpenes acids isolated from Miconia species

et al. 2013

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“…In modern drug discovery campaign, the process usually starts from an unmet clinical need (disease), followed by target identification and validation, high-throughput screening (HTS) and/or in silico-in vitro screening to identify hit compounds, hit-to-lead and lead optimizations, clinical trials up to the approved drug (Figures 2.1 and 2.2) [2][3][4].…”

Section: Drug Discoverymentioning

confidence: 99%