How proteins bind macrocycles

Villar, Elizabeth A.; Beglov, Dmitri; Chennamadhavuni, Spandan; Porco, John A.; Kozakov, Dima; Vajda, Sándor; Whitty, Adrian

doi:10.1038/nchembio.1584

Cited by 357 publications

(429 citation statements)

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“…To achieve all three of these goals without compromising synthetic efficiency or relevance to complex natural products, we were attracted to cyclodepsipeptides, in which biological activity is quite diverse (18)(19)(20)(21)(22)(23). Herein, we report rapid access to size-diverse collections of cyclooligodepsipeptides using a controlled oligomerization/macrocyclization sequence.…”

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confidence: 99%

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Batiste

Johnston

2016

Proc. Natl. Acad. Sci. U.S.A.

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Macrocyclic small molecules are attractive tools in the development of sensors, new materials, and therapeutics. Within early-stage drug discovery, they are increasingly sought for their potential to interact with broad surfaces of peptidic receptors rather than within their narrow folds and pockets. Cyclization of linear small molecule precursors is a straightforward strategy to constrain conformationally mobile motifs, but forging a macrocycle bond typically becomes more difficult at larger ring sizes. We report the development of a general approach to discrete collections of oligomeric macrocyclic depsipeptides using an oligomerization/macrocyclization process governed by a series of Mitsunobu reactions of hydroxy acid monomers. Ring sizes of 18, 24, 30, and 36 are formed in a single reaction from a didepsipeptide, whereas sizes of 24, 36, and 60 result from a tetradepsipeptide. The ring-size selectivity inherent to the approach can be modulated by salt additives that enhance the formation of specific ring sizes. Use of chemical synthesis to prepare the monomers suggests broad access to functionally and stereochemically diverse collections of natural product-like oligodepsipeptide macrocycles. Two cyclodepsipeptide natural products were prepared along with numerous unnatural oligomeric congeners to provide rapid access to discrete collections of complex macrocyclic small molecules from medium (18) to large (60) ring sizes.Mitsunobu | total synthesis | collective | macrocycle | oligomerization I nterest in the preparation and use of small molecules exhibiting macrocyclic rings is growing at a tremendous pace, driving the development of new approaches, new chemical reactions, and the underlying chemistry and tools (catalysts) to support them. Historically, studies of macrocyclization reactions have been guided by natural products bearing unusually large carbocycles or mediumand large-ring lactones, amides, and ethers. Fragmentation reactions of polycyclic molecules have long played a role in access to medium-sized macrocycles, whereas macrocyclizations to lactones and amides are often accomplished from linear precursors at high dilution. Insofar as these efforts were typically driven by the goal to prepare a specific macrocycle, often in the form relevant to a natural product synthesis or an engineered constraint to a peptide, absent from the field is an approach that provides rapid access to collections (1) of natural product-like macrocycles, particularly from stereochemically complex, functionally rich, linear precursors (2-6).Pioneers in this area have recorded some success (Fig. 1). Esterification reactions of activated hydroxy acids have led predominantly to diolides, (7-10) and in a single case, oligolides (11). Amidation reactions of activated polypeptides were central to the preparations of macrocyclic peptides by Rothe and Kreiss (12,13) and Wipf and coworkers (14, 15), but they were low yielding and size nonselective. Burke and coworkers (16,17) have shown that the efficiency of an 18-membered oligol...

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confidence: 99%

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Batiste

Johnston

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Consequently, they usually have lower ligand efficiencies when binding to flator groove-shaped sites than traditional Ro5 compliant drugs binding to pockets or internal sites; an observation that should be kept in mind when prioritizing ligands for difficult targets [5]. Importantly, the physicochemical nature of bRo5 drugbinding interfaces are similar to the surface of the compounds as a whole, and to the surface of Ro5 compliant drugs, suggesting that the same approaches for property-based lead optimization can be used in both chemical spaces [3,5].…”

Section: Opportunities For Difficult Targetsmentioning

confidence: 99%

“…In addition, rod-shaped non-macrocyclic compounds in bRo5 space are ideal for binding to large grooveshaped binding sites, for instance those of PPI [4]. Independent of their chemotype, oral drugs in bRo5 space may bury up to 800-900 Å 2 of ligand surface area when binding to their target, that is, a surface area approaching that of a PPI interface [3,5]. Just as regular Ro5 compliant drugs, drugs in bRo5 space usually display a K d /IC 50 of 1-100 nM for binding to their targets.…”

Section: Opportunities For Difficult Targetsmentioning

confidence: 99%

“…For example, a number of prominent oral drug classes used as antibacterials, antivirals, antifungals, immunosuppressants, and anticancer agents exist in bRo5 space. Macrocycles provide unique advantages to modulate targets that have flat or shallow groove-shaped binding sites [3,5]. In addition, rod-shaped non-macrocyclic compounds in bRo5 space are ideal for binding to large grooveshaped binding sites, for instance those of PPI [4].…”

Section: Opportunities For Difficult Targetsmentioning

confidence: 99%

“…Recent reviews have emphasized that target classes that have difficult large, flat, or groove-shaped binding sites such as protein-protein interactions (PPIs), proteases, transferases, and some other nontraditional drug targets may preferentially be modulated by compounds in chemical space beyond the Ro5 (bRo5, Figure 1(a)) [3][4][5]. For example, a number of prominent oral drug classes used as antibacterials, antivirals, antifungals, immunosuppressants, and anticancer agents exist in bRo5 space.…”

Section: Opportunities For Difficult Targetsmentioning

confidence: 99%

See 2 more Smart Citations

Drug discovery beyond the rule of 5 - Opportunities and challenges

Doak

Kihlberg

2016

Expert Opinion on Drug Discovery

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Drug Discovery Beyond the Rule of Five

DeGoey

Cox

2021

Burger's Medicinal Chemistry and Drug Discovery

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Approximately 6% of orally administered drugs have physicochemical properties that are beyond Lipinski's rule of five (bRo5). However, in the past five years, there have been 22 new oral bRo5 drugs approved by the FDA, which account for 21% of new oral drug approvals. The significant increase in the percentage of bRo5 drug approvals represents a shift in the types of drug targets undertaken by medicinal chemists including a larger number of protein–protein interaction (PPI) inhibitors, such as BCL‐2 inhibitors, and nontraditional drug targets such as NS5A inhibitors for the treatment of hepatitis C (HCV). The shift away from more druggable enzyme and GPCR targets has resulted in the development of larger molecules that have physicochemical properties that far exceed those previously expected to yield adequate solubility and permeability for oral absorption. Due to frequently lower solubility and permeability, conducting drug discovery research in bRo5 chemical space is difficult and represents a challenge for medicinal chemists to move away from the more well‐understood Ro5 chemical space. In this article, we review the current state of the art for drug discovery bRo5 including a review of the literature, an analysis of physicochemical properties and case studies of the approved classes of bRo5 drugs.

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How proteins bind macrocycles

Cited by 357 publications

References 53 publications

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Rapid synthesis of cyclic oligomeric depsipeptides with positional, stereochemical, and macrocycle size distribution control

Drug discovery beyond the rule of 5 - Opportunities and challenges

Drug Discovery Beyond the Rule of Five

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