Second-generation de novo design: a view from a medicinal chemist perspective

Zaliani, Andrea; Boda, Krisztina; Seidel, Thomas; Herwig, Achim; Schwab, Christof H.; Gasteiger, Johann; Claußen, Holger; Lemmen, Christian; Degen, Jörg; Pärn, Juri; Rarey, Matthias

doi:10.1007/s10822-009-9291-2

Cited by 30 publications

(17 citation statements)

References 19 publications

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“…Many successful applications of de novo design methods have also been reported so far. 12,17 No matter what lead optimization is performed by human experts or with the aid of computer programs, the outcomes of the virtual screening job conducted at the previous lead discovery stage are not useful any more. Virtual screening often requires high-performance computing facilities since hundreds of thousands of molecules need to be examined through extensive molecular docking to the target protein.…”

mentioning

confidence: 99%

Automatic Tailoring and Transplanting: A Practical Method that Makes Virtual Screening More Useful

Zhao

Liu

et al. 2011

J. Chem. Inf. Model.

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Docking-based virtual screening of large compound libraries has been widely applied to lead discovery in structure-based drug design. However, subsequent lead optimizations often rely on other types of computational methods, such as de novo design methods. We have developed an automatic method, namely automatic tailoring and transplanting (AutoT&T), which can effectively utilize the outcomes of virtual screening in lead optimization. This method detects suitable fragments on virtual screening hits and then transplants them onto a lead compound to generate new ligand molecules. Binding affinities, synthetic feasibilities, and drug-likeness properties are considered in the selection of final designs. In this study, our AutoT&T program was tested on three different target proteins, including p38 MAP kinase, PPAR-α, and Mcl-1. In the first two cases, AutoT&T was able to produce molecules identical or similar to known inhibitors with better potency than the given lead compound. In the third case, we demonstrated how to apply AutoT&T to design novel ligand molecules from scratch. Compared to the solutions generated by other two de novo design methods, i.e., LUDI and EA-Inventor, the solutions generated by AutoT&T were structurally more diverse and more promising in terms of binding scores in all three cases. AutoT&T also completed the assigned jobs more efficiently than LUDI and EA-Inventor by several folds. Our AutoT&T method has certain technical advantages over de novo design methods. Importantly, it expands the application of virtual screening from lead discovery to lead optimization and thus may serve as a valuable tool for many researchers.

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mentioning

confidence: 99%

Automatic Tailoring and Transplanting: A Practical Method that Makes Virtual Screening More Useful

Zhao

Liu

et al. 2011

J. Chem. Inf. Model.

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“…Zaliani et al developed a software suite for fragmentbased DND called NovoBench, including CoLibri, Recore, FragView, FragEnum, FlexNovo and Sylvia softwares [124]. One of these tools, Recore, has been developed to perform scaffold hopping [125].…”

Section: De Novo Designmentioning

confidence: 99%

Fragment-Based Drug Design: Computational and Experimental State of the Art

Hoffer¹,

Renaud²,

Horvath

2011

CCHTS

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Fragment-based screening is an emerging technology which is used as an alternative to high-throughput screening (HTS), and often in parallel. Fragment screening focuses on very small compounds. Because of their small size and simplicity, fragments exhibit a low to medium binding affinity (mM to µM) and must therefore be screened at high concentration in order to detect binding events. Since some issues are associated with high-concentration screening in biochemical assays, biophysical methods are generally employed in fragment screening campaigns. Moreover, these techniques are very sensitive and some of them can give precise information about the binding mode of fragments, which facilitates the mandatory hit-to-lead optimization. One of the main advantages of fragment-based screening is that fragment hits generally exhibit a strong binding with respect to their size, and their subsequent optimization should lead to compounds with better pharmacokinetic properties compared to molecules evolved from HTS hits. In other words, fragments are interesting starting points for drug discovery projects. Besides, the chemical space of low-complexity compounds is very limited in comparison to that of drug-like molecules, and thus easier to explore with a screening library of limited size. Furthermore, the "combinatorial explosion" effect ensures that the resulting combinations of interlinked binding fragments may cover a significant part of "drug-like" chemical space. In parallel to experimental screening, virtual screening techniques, dedicated to fragments or wider compounds, are gaining momentum in order to further reduce the number of compounds to test. This article is a review of the latest news in both experimental and in silico virtual screening in the fragment-based discovery field. Given the specificity of this journal, special attention will be given to fragment library design.

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“…Synthetic accessibility of these optimized compounds was checked using SYLVIA, version 1.0 [58,59] from the Molecular Networks group. The estimation of synthetic accessibility using SYLVIA provides values between 1 for compounds that are very easy to synthesize and 10 for compounds that are very difficult to synthesize.…”

Section: Optimization Of Final Hit Compoundmentioning

confidence: 99%

“…The best pharmacophore model, Hypo1, was used as a 3D query to search three chemical databases, NCI (260,071 compounds), Maybridge (59,632) and Chembridge (50,000), for a total of 369,703 compounds. The Ligand Pharmacophore Mapping protocol with the Best Flexible Search option was employed to search these databases.…”

Section: Database Screening and Drug-likeness Predictionmentioning

confidence: 99%