Scaffold selection and scaffold hopping in lead generation: a medicinal chemistry perspective

Zhao, Hongyu

doi:10.1016/j.drudis.2006.12.003

Cited by 138 publications

(98 citation statements)

References 36 publications

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“…org). Multiple, unrelated scaffolds are generally considered necessary because of attrition in hit-to-lead chemistry as a result of issues with chemical tractability for lead optimization, pharmacokinetic liabilities, specificity for the desired target, cost, and other factors (Zhao, 2007). Second, drug discovery will be assisted by our single-channel studies, which provide mechanistic insights into how derivatives may achieve greater potency.…”

Section: Discussionmentioning

confidence: 99%

A Cell-Based High-Throughput Screen Validates the Plasmodial Surface Anion Channel As an Antimalarial Target

Pillai¹,

Pain²,

Solomon³

et al. 2010

Mol Pharmacol

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The plasmodial surface anion channel (PSAC) is an unusual small-conductance ion channel induced on erythrocytes infected with plasmodia, including parasites responsible for human malaria. Although broadly available inhibitors produce microscopic clearance of parasite cultures at high concentrations and suggest that PSAC is an antimalarial target, they have low affinity for the channel and may interfere with other parasite activities. To address these concerns, we developed a miniaturized assay for PSAC activity and carried out a high-throughput inhibitor screen. Approximately 70,000 compounds from synthetic and natural product libraries were screened, revealing inhibitors from multiple structural classes including two novel and potent heterocyclic scaffolds. Single-channel patch-clamp studies indicated that these compounds act directly on PSAC, further implicating a proposed role in transport of diverse solutes. A statistically significant correlation between channel inhibition and in vitro parasite killing by a family of compounds provided chemical validation of PSAC as a drug target. These new inhibitors should be important research tools and may be starting points for much-needed antimalarial drugs.

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Section: Discussionmentioning

confidence: 99%

A Cell-Based High-Throughput Screen Validates the Plasmodial Surface Anion Channel As an Antimalarial Target

Pillai¹,

Pain²,

Solomon³

et al. 2010

Mol Pharmacol

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“…The ability to identify such novel ring-systems, an ability that is often referred to as scaffold hopping or lead hopping, is a key capability of an effective method for virtual screening [6][7][8][9]. Bohm et al state that "The aim of scaffold hopping is to discover structurally novel compounds starting from known active compounds by modifying the central core structure of the molecule" [10]; and in like vein, Zhou defines scaffold hopping as "a computational technique that identifies a topologically different scaffold from the parent compound but with similar or improved activity and other properties from a given database" [11]. Scaffold hopping is important for three principal reasons: it can provide a back-up if the existing lead series in a project subsequently proves to exhibit poor ADMET properties; some positions around a given scaffold may be synthetically difficult, where as an alternative may enable the creation of the desired substitution pattern; most importantly, it provides a way of circumventing the structural coverage of an existing, competitor patent.…”

Section: Introductionmentioning

confidence: 99%

Effectiveness of 2D Fingerprints for Scaffold Hopping

et al. 2011

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Universities of LeedsMethods. This paper reports a detailed evaluation of the effectiveness of six common types of 2D fingerprint when they are used for scaffold hopping similarity searches of MDDR, WOMBAT and MUV data.Results. The results demonstrate that 2D fingerprints can be used for scaffold hopping, with novel scaffolds being identified in nearly every search that was carried out. The degree of enrichment depends on the structural diversity of the actives that are being sought, with the greatest enrichments often being obtained using ECFP4 fingerprints. Conclusions. 2D fingerprints provide a simple, and computationally efficient, way of identifying novel chemotypes in lead-discovery programmes.

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“…The identification of promising hits and the generation of high quality leads are crucial steps in the early stages of drug discovery [1][2][3]. Advances in medicinal chemistry at the interface of chemistry and biology have created an important foundation in the search for new drug candidates possessing a combination of optimized pharmacodynamic and pharmacokinetic properties.…”

Section: Introductionmentioning

confidence: 99%

Fragment-based QSAR: perspectives in drug design

Salum

Andricopulo

2009

Mol Divers

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Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. Quantitative structure-activity relationship (QSAR) methods are among the most important strategies that can be applied for the successful design of small molecule modulators having clinical utility. Hologram QSAR (HQSAR) is a modern 2D fragment-based QSAR method that employs specialized molecular fingerprints. HQSAR can be applied to large data sets of compounds, as well as traditional-size sets, being a versatile tool in drug design. The HQSAR approach has evolved from a classical use in the generation of standard QSAR models for data correlation and prediction into advanced drug design tools for virtual screening and pharmacokinetic property prediction. This paper provides a brief perspective on the evolution and current status of HQSAR, highlighting present challenges and new opportunities in drug design.

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Scaffold selection and scaffold hopping in lead generation: a medicinal chemistry perspective

Cited by 138 publications

References 36 publications

A Cell-Based High-Throughput Screen Validates the Plasmodial Surface Anion Channel As an Antimalarial Target

A Cell-Based High-Throughput Screen Validates the Plasmodial Surface Anion Channel As an Antimalarial Target

Effectiveness of 2D Fingerprints for Scaffold Hopping

Fragment-based QSAR: perspectives in drug design

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