Rapid in silico selection of an MCHR1 antagonists’ focused library from multi-million compounds’ repositories: biological evaluation

Flachner, Beáta; Tömöri, Tünde; Hajdú, István; Dobi, Krisztina; Lőrincz, Zsolt; Cseh, Sándor; Dormán, György

doi:10.1007/s00044-013-0695-0

Cited by 4 publications

(5 citation statements)

References 24 publications

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“…This concept is well known in many scientific fields, where a number of definitions are limited when the service or product is received and meets the expectations expected by the client, including satisfaction of the needs and desires associated with the purchase process (Kotler et al, 2002). Bitner and Hubbert (1994) confirmed that the satisfaction is linked to customer service evaluation where it achieves his/her needs and wants, therefore, the companies nowadays focus on customer satisfaction and they work to study and analysis the customer behavior and his attitude from the service and extent of it.…”

Section: Customer Satisfactionmentioning

confidence: 99%

The impact of quality of services and satisfaction on customer loyalty: The moderate role of switching costs

Harazneh¹,

Adaileh²,

Thbeitat³

et al. 2020

10.5267/j.msl

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This study investigates the impacts of service quality of Jordanian telecommunication and customer satisfaction on customer loyalty. The study also studies though the role of switching cost as a moderate variable. Lack of studies in the field of quality in Jordanian telecommunication is the main reason for this investigation. The study investigates the impacts based on the employees' point of views in Aqaba special economic zone authority (ASEZA). Therefore, the study uses statistical data gathered through a questionnaire distributed to the employees of ASEZA. Thus, statistical methods are used to analyze the data collected and the hypotheses are tested. The study results show that there was a direct positive impact of service quality of Jordanian telecommunication and customer satisfaction on customer loyalty. In addition, the moderator model (Switching cost) has significant positive impacts on enhancing the relationship between service quality and customer satisfaction towards customer loyalty.

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Section: Customer Satisfactionmentioning

confidence: 99%

The impact of quality of services and satisfaction on customer loyalty: The moderate role of switching costs

Harazneh¹,

Adaileh²,

Thbeitat³

et al. 2020

10.5267/j.msl

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“…One of the critical issues in 2D ligand-based similarity selection approaches is the novelty vs. similarity [41], thus, structural analysis of the hits is a necessary task after biological evaluation of the focused library. Novelty could mean different core structure (scaffold/chemotype) or in the case of linear compounds a different arrangement of the various motifs although in a different substitution pattern [42]. After diversity selection and visual inspection, we purchased 50 compounds, which contained 1,2,3-benzotriazoles (16), 1,2,4-triazoles (15), imidazoles (6), 3,1-benzoxazin-4-ones (5) and five unrelated (novel) chemotypes (see Supplementary Materials, Tables S2–S4) at T ≥ 0.65 Tanimoto similarity level.…”

Section: Discussionmentioning

confidence: 99%

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

Szilágyi¹,

Hajdú

Flachner³

et al. 2019

Molecules

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The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade. Designing C1 inhibitors is particularly challenging since known inhibitors are restricted to a narrow bioactive chemical space in addition selectivity over other serine proteases is an important requirement. The typical architecture of a small molecule inhibitor of C1s contains an amidine (or guanidine) residue, however, the discovery of non-amidine inhibitors might have high value, particularly if novel chemotypes and/or compounds displaying improved selectivity are identified. We applied various virtual screening approaches to identify C1s focused libraries that lack the amidine/guanidine functionalities, then the in silico generated libraries were evaluated by in vitro biological assays. While 3D structure-based methods were not suitable for virtual screening of C1s inhibitors, and a 2D similarity search did not lead to novel chemotypes, pharmacophore model generation allowed us to identify two novel chemotypes with submicromolar activities. In three screening rounds we tested altogether 89 compounds and identified 20 hit compounds (<10 μM activities; overall hit rate: 22.5%). The highest activity determined was 12 nM (1,2,4-triazole), while for the newly identified chemotypes (1,3-benzoxazin-4-one and thieno[2,3-d][1,3]oxazin-4-one) it was 241 nM and 549 nM, respectively.

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“…The selected compounds mainly reflected the parent (seed) compounds’ architecture. In our previous studies, we experienced only swapping of the fragments with linear molecules as primary changes at T > 0.65 similarity level .…”

Section: Discussionmentioning

confidence: 99%

“…Due to the fact that random screening of a discovery library often results in a poor hit rate (≤0.1%), we have decided to select 5‐HT 6 target‐focused libraries for screening. We applied a two‐stage focused library selection strategy that we successfully validated earlier . In the first‐round screening, we selected the focused library by 2D similarity selection and property‐based filtering around the structure of biologically active reference compounds.…”

mentioning

confidence: 99%

Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5‐HT₆ Antagonists from Large Commercial Repositories

Dobi¹,

Flachner²,

Pukáncsik³

et al. 2015

Chem Biol Drug Des

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Rapid in silico selection of target-focused libraries from commercial repositories is an attractive and cost-effective approach. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compound databases, but the generated library requires further focusing. We report here a combination of the 2D approach with pharmacophore matching which was used for selecting 5-HT6 antagonists. In the first screening round, 12 compounds showed >85% antagonist efficacy of the 91 screened. For the second-round (hit validation) screening phase, pharmacophore models were built, applied, and compared with the routine 2D similarity search. Three pharmacophore models were created based on the structure of the reference compounds and the first-round hit compounds. The pharmacophore search resulted in a high hit rate (40%) and led to novel chemotypes, while 2D similarity search had slightly better hit rate (51%), but lacking the novelty. To demonstrate the power of the virtual screening cascade, ligand efficiency indices were also calculated and their steady improvement was confirmed.

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Rapid in silico selection of an MCHR1 antagonists’ focused library from multi-million compounds’ repositories: biological evaluation

Cited by 4 publications

References 24 publications

The impact of quality of services and satisfaction on customer loyalty: The moderate role of switching costs

The impact of quality of services and satisfaction on customer loyalty: The moderate role of switching costs

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5‐HT₆ Antagonists from Large Commercial Repositories

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Rapid in silico selection of an MCHR1 antagonists’ focused library from multi-million compounds’ repositories: biological evaluation

Cited by 4 publications

References 24 publications

The impact of quality of services and satisfaction on customer loyalty: The moderate role of switching costs

The impact of quality of services and satisfaction on customer loyalty: The moderate role of switching costs

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5‐HT6 Antagonists from Large Commercial Repositories

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Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5‐HT₆ Antagonists from Large Commercial Repositories