Properties Guiding Drug‐ and Lead‐Likeness

Mureşan, Sorel; Sadowski, Jens

doi:10.1002/9783527621286.ch17

Cited by 10 publications

(3 citation statements)

References 57 publications

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“…A good PK-profile of drug-likeness is the normal first filter for screening databases, ,, because selecting drug-like compounds enhances the possibility to achieve relevant hits. Therefore the database was restricted exclusively to compounds with drug-like properties.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Novel and Cardioselective Diltiazem-like Calcium Channel Blockers via Virtual Screening

et al. 2008

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With the effort to discover new chemotypes blocking L-type calcium channels (LTCCs), ligand-based virtual screening was applied with a specific interest toward the diltiazem binding site. Roughly 50000 commercially available compounds served as a database for screening. The filtering through predicted pharmacokinetic properties and structural requirements reduced the initial database to a few compounds for which the similarity was calculated toward two template molecules, diltiazem and 4-chloro-Ncyclopropyl- N-(4-piperidinyl)benzene-sulfonamide, the most interesting hit of a previous screening experiment. For 18 compounds, inotropic and chronotropic activity as well as the vasorelaxant effect on guinea pig were studied "in vitro", and for the most promising, binding studies to the diltiazem site were carried out. The procedure yielded several hits, confirming in silico techniques to be useful for finding new chemotypes. In particular, N-[2-(dimethylamino)ethyl]-3-hydroxy-2-naphthamide, N,Ndimethyl- N'-(2-pyridin-3-ylquinolin-4-yl)ethane-1,2-diamine, 2-[(4-chlorophenyl)(pyridin-2-yl)methoxy]- N,N-dimethylethanamine (carbinoxamine), and 7-[2-(diethylamino)ethoxy]-2H-chromen-2-one revealed interesting activity and binding to the benzothiazepine site.

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Section: Resultsmentioning

confidence: 99%

Discovery of Novel and Cardioselective Diltiazem-like Calcium Channel Blockers via Virtual Screening

et al. 2008

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“…These include diversity, biological relevance, and compound quality [121][122][123][124][125]. Retrospective analyses with regard to druglikeness, lead-likeness, or biological relevance may help to evaluate and increase the quality of a compound library [126][127][128][129][130][131][132][133]. NPs can be seen as one particular group of compounds endowed with special properties and biological relevance, since NPs have been selected during evolution to bind to proteins, for example, during biosynthesis or while fulfilling their biological role as a second messenger, hormone, or venom [134][135][136].…”

Section: Exploiting Natural Product Chemical Space For Medicinal Chemmentioning

confidence: 99%

Role of Natural Products in Drug Discovery

Lachance

Wetzel

Waldmann

2010

Lead Generation Approaches in Drug Discovery

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“…Lipinski’s rule of five [9], which relates solubility, partition coefficient (logP), molecular weight, and the number of hydrogen bond donors and acceptors with known drug activity, is a standard approach to eliminate undesirable compounds from a chemical library [10]. Nevertheless, computational parameters used to characterize drug-like chemical properties continue to evolve [11], where there are additional concerns of being too restrictive to novel compound classes [6]. Alternatively, virtual screens are routinely used to predict likely active compounds to design a chemical library for HTS [12-14].…”

Section: Introductionmentioning

confidence: 99%

The Applicability of Molecular Descriptors for Designing an Electrospray Ionization Mass Spectrometry Compatible Library for Drug Discovery

Copeland

Zehr

Cerny³

et al. 2012

CCHTS

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Detecting a small molecular-weight compound by electrospray ionization mass spectrometry (ESI-MS) requires the compound to obtain a charge. Factors such as gas-phase proton affinities and analyte surface activity are correlated with a positive ESI-MS response, but unfortunately it is extremely challenging to predict from a chemical structure alone if a compound is likely to yield an observable molecular-ion peak in an ESI-MS spectrum. Thus, the design of a chemical library for an ESI-MS ligand-affinity screen is particularly daunting. Only 56.9% of the compounds from our FAST-NMR functional library [1] were detectable by ESI-MS. An analysis of ~1,600 molecular descriptors did not identify any correlation with a positive ESI-MS response that cannot be attributed to a skewed population distribution. Unfortunately, our results suggest that molecular descriptors are not a valuable approach for designing a chemical library for an MS-based ligand affinity screen.

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Properties Guiding Drug‐ and Lead‐Likeness

Cited by 10 publications

References 57 publications

Discovery of Novel and Cardioselective Diltiazem-like Calcium Channel Blockers via Virtual Screening

Discovery of Novel and Cardioselective Diltiazem-like Calcium Channel Blockers via Virtual Screening

Role of Natural Products in Drug Discovery

The Applicability of Molecular Descriptors for Designing an Electrospray Ionization Mass Spectrometry Compatible Library for Drug Discovery

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