Artificial macrocycles as IL-17A/IL-17RA antagonists

The replica exchange molecular dynamics (REMD) simulation is demonstrated to readily predict the conformations of the macrocyclic drug lorlatinib, as validated by solution NMR studies. In aqueous solution, lorlatinib adopts a conformer identical to its target bound structure. This conformer is stabilized by an extensive hydrogen bond network to the solvents. In chloroform, lorlatinib populates two conformers with the second one being less polar, which may contribute to lorlatinib’s ability to cross cell membranes.

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“…15,16 Recently macrocyclic drugs have been reported to target a variety of PPIs, such as MDM2/p53, 17 BCL-2, 18 and IL-17A/IL-17RA. 19…”

Section: Introductionmentioning

confidence: 99%

Conformation of the Macrocyclic Drug Lorlatinib in Polar and Nonpolar Environments: A MD Simulation and NMR Study

et al. 2019

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“… 24 We have recently described multiple scaffolds of artificial macrocycles which are readily synthesizable using multicomponent reaction chemistry (MCR) 25 − 30 and investigated the structural basis of macrocycles targeting PD1–PDL1, p53–MDM2, and IL17A receptor interactions. 30 − 33 Thus, we are highly interested in computational tools to rapidly screen conformational space of large virtual macrocycle libraries as a filter to synthesize bioactive compounds. To date, several benchmarks demonstrated the feasibility of algorithms with the aim of producing macrocycle conformations with enough accuracy and uniqueness for common computer-aided drug design (CADD) strategies, such as docking and pharmacophore screening.…”

Section: Introductionmentioning

confidence: 99%

Benchmark of Generic Shapes for Macrocycles

Romero

Ruiz-Moreno

Groves

et al. 2020

J. Chem. Inf. Model.

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Macrocycles target proteins that are otherwise considered undruggable because of a lack of hydrophobic cavities and the presence of extended featureless surfaces. Increasing efforts by computational chemists have developed effective software to overcome the restrictions of torsional and conformational freedom that arise as a consequence of macrocyclization. Moloc is an efficient algorithm, with an emphasis on high interactivity, and has been constantly updated since 1986 by drug designers and crystallographers of the Roche biostructural community. In this work, we have benchmarked the shape-guided algorithm using a dataset of 208 macrocycles, carefully selected on the basis of structural complexity. We have quantified the accuracy, diversity, speed, exhaustiveness, and sampling efficiency in an automated fashion and we compared them with four commercial (Prime, MacroModel, molecular operating environment, and molecular dynamics) and four open-access (experimental-torsion distance geometry with additional “basic knowledge” alone and with Merck molecular force field minimization or universal force field minimization, Cambridge Crystallographic Data Centre conformer generator, and conformator) packages. With three-quarters of the database processed below the threshold of high ring accuracy, Moloc was identified as having the highest sampling efficiency and exhaustiveness without producing thousands of conformations, random ring splitting into two half-loops, and possibility to interactively produce globular or flat conformations with diversity similar to Prime, MacroModel, and molecular dynamics. The algorithm and the Python scripts for full automatization of these parameters are freely available for academic use.

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“…An example of an artificial macrocycle binding to the interface of the IL17 dimer is shown in Figure 3. 5…”

Section: Macrocycle Properties and Receptor Bindingmentioning

confidence: 99%

Artificial Macrocycles

Abdelraheem

Shaabani

Dömling

2018

Synlett

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Artificial macrocycles recently became popular as a novel research field in drug discovery. As opposed to their natural twins, artificial macrocycles promise to have better control on synthesizability and control over their physicochemical properties resulting in druglike properties. Very few synthetic methods allow for the convergent, fast but diverse access to large macrocycles chemical space. One synthetic technology to access artificial macrocycles with potential biological activity, multicomponent reactions, is reviewed here, with a focus on our own work. We believe that synthetic chemists have to acquaint themselves more with structure and activity to leverage the design aspect of their daily work.

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Artificial macrocycles as IL-17A/IL-17RA antagonists

Cited by 21 publications

References 25 publications

Conformation of the Macrocyclic Drug Lorlatinib in Polar and Nonpolar Environments: A MD Simulation and NMR Study

Conformation of the Macrocyclic Drug Lorlatinib in Polar and Nonpolar Environments: A MD Simulation and NMR Study

Benchmark of Generic Shapes for Macrocycles

Artificial Macrocycles

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