Computer-assisted synthetic analysis. Performance of tactical combinations of transforms

Long, Alan K.; Kappos, John C.

doi:10.1021/ci00020a028

Cited by 14 publications

(12 citation statements)

References 5 publications

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“…The work by Kappos and Long, 95,96 in preassembling TCs of transforms as reusable synthetic templates, was demonstrated as providing another powerful technique able to apply a deeper analysis to a complex synthetic problem. There are now realistic opportunities to automate the discovery of many reusable TCs via the algorithmic analysis of published syntheses captured in today's large and comprehensive reaction databases.…”

Section: Discussionmentioning

confidence: 99%

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Computer‐aided synthesis design: 40 years on

Cook

Johnson

Law³

et al. 2011

WIREs Comput Mol Sci

101

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The discipline of retrosynthetic analysis is now just over 40 years old. From the earliest day, attempts were made to incorporate this approach into computer programs to test the extent in which chemical perception and synthetic thinking could be formalized. Despite pioneering research efforts, computer‐aided synthetic analysis failed to achieve widespread routine use by chemists, which can be attributed in part to the difficulty of building the required high‐quality retrosynthetic transform databases required for credible analyses. However, with the advent over the past 25 years of large comprehensive reaction databases, work on successfully automating the construction of reliable and comprehensive reaction rule databases is promising to revitalize research in this field. This review compares and contrasts the diverse approaches taken by selected programs in both the design and implementation of molecule feature perception and reaction rule representation, and we review the concepts of synthetic strategy selection, representation, and execution. In particular, we discuss the current work on automating the construction of reliable and comprehensive synthetic rule sets from available reaction databases in newer programs such as ARChem. We argue that the progress achieved in this aspect paves the way to a deeper exploration of computer approaches to applying strategy and control in the synthesis problem. © 2011 John Wiley & Sons, Ltd. This article is categorized under: Computer and Information Science > Chemoinformatics

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Section: Discussionmentioning

confidence: 99%

“…The change code mechanism was used to efficiently select the individual transforms needed to execute a particular tactical combination (TC) ( vide infra ) 95,96. The LHASA transform compiler was updated to compute change codes for each transform.…”

Section: Reaction Representationmentioning

confidence: 99%

Computer‐aided synthesis design: 40 years on

Cook

Johnson

Law³

et al. 2011

WIREs Comput Mol Sci

101

View full text Add to dashboard Cite

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“…For this step, the complexity change compared to the target (and, of course, the intermediate) is negative, DC 2 = C substrate À C target < 0. We observe that these definitions are more stringent than for some of the TCs Corey cataloged 3,11 ; therein, both steps could simplify the structure. However, such monotonic-complexity-decrease combinations of steps are, arguably, easily identified while enabling the other.…”

Section: Figure 2 Quantification Of and Searches For Tactical Combinationsmentioning

confidence: 91%

“…When planning syntheses of complex organic molecules, it is often not sufficient to gradually simplify the structure-instead, it may be beneficial to go through an intermediate that does not, per se, produce any immediate gain (or even intermittently increases structural complexity) but sets the scene for a ''downstream'' disconnection offering a significant structural simplification (Figures 1 and 2A). A few decades ago, Corey and Cheng 1 christened such sequences as ''tactical combinations'' (TCs)-since then, some of them have become a part of mainstream retrosynthetic thinking [2][3][4][5][6] (Figures 1A and 1B), some are less obvious and require a trained eye to spot 7,8 (Figures 1C-1E), and yet some others, used as key steps in syntheses of complex natural products, are truly remarkable, making one wonder how the authors were inspired to identify such an elegant combination 9,10 (Figures 1F and 1G). Indeed, the notion that TCs are ''inspired'' rather than ''discovered'' is reinforced by the fact that the largest collection cataloged in Ott 11 provides only ca.…”

Section: Introductionmentioning

confidence: 99%

Algorithmic Discovery of Tactical Combinations for Advanced Organic Syntheses

Gajewska

Szymkuć

Dittwald

et al. 2020

Chem

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Tactical combinations (TCs) are two-step reaction sequences that first, in a retrosynthetic direction, complexify the target structure but, by doing so, enable significant structural simplification in subsequent steps. TCs are often hard to identify, and only a few hundred have been cataloged to date. This work shows that computers can now discover TCs having no literature precedent systematically and in large numbers, in effect unlocking new and elegant synthetic approaches.

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“…The development of computer-aided toxicity prediction techniques can be based on QSAR models or expert systems [132][133][134][135][136]. Also, synthesizability [137][138] and shelf life could be converted into useful computational filters for improving the efficiency of lead prediction protocols.…”

Section: Drug-like Filtersmentioning

confidence: 99%

A Binding Affinity Based Computational Pathway for Active-Site Directed Lead Molecule Design: Some Promises and Perspectives

Latha¹,

Jayaram

2005

DDRO

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Drug discovery in the 21 st century is expected to be different in at least two distinct ways: development of individualized medicine utilizing genomic information and emergence of an integrated in silico protocol for facilitating target identification, structure prediction and lead discovery. The expectations from computational methods for developing suggestions on potential leads reliably and expeditiously, are continuously on the increase. Several conceptual and methodological concerns remain before an automation of lead design in silico could be contemplated. The novelty of the candidates generated, their geometries, the partial atomic charges and other force field parameters for enabling energy evaluations is one concern. A proper account of the flexibility of the candidate molecule and the target, a consideration of solvent and salt effects in binding and a reliable methodology for developing quantitative estimates of binding affinities is another. Finally the drug-likeness of the candidates generated is yet another concern. Each of these issues warrants a careful consideration. In this review, we sketch a system independent, binding free energy based, comprehensive computational pathway from chemical templates to lead-like molecules, given the three dimensional structure of the target protein and a definition of its active site, focusing on some emerging in silico trends and techniques. We survey current methods for generation of candidate molecules and some popular protocols for docking candidates in the protein active site. We discuss the theory of protein-ligand binding in the rigorous framework of statistical mechanics and assess the current strategies for affinity based filtering of candidates. We address concerns related to flexibility of the target and the candidate, solvent and salt effects in lead design. We present a realization of the pathway proposed in a high performance computing environment for cyclooxygenase-2 target wherein the computational protocols could sort drugs from nondrugs, assuring the viability of the overall strategy. We highlight a few case studies indicating the current level of agreement between theory and experiment in eliciting binding affinities. Finally, we present a critical assessment of the computational steps involved in binding affinity based active site directed lead molecule design and further improvements envisioned for potential automation.

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Computer-assisted synthetic analysis. Performance of tactical combinations of transforms

Cited by 14 publications

References 5 publications

Computer‐aided synthesis design: 40 years on

Computer‐aided synthesis design: 40 years on

Algorithmic Discovery of Tactical Combinations for Advanced Organic Syntheses

A Binding Affinity Based Computational Pathway for Active-Site Directed Lead Molecule Design: Some Promises and Perspectives

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