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    Drug discovery is a laborious process with rising cost per new drug. Peptide macrocycles are promising therapeutics, though conformational flexibility can reduce target affinity and specificity. Recent computational advancements address this problem by enabling rational design of rigidly folded peptide macrocycles. This review summarizes currently approved peptide macrocycle therapeutics and discusses advantages of mesoscale drugs over small molecules or protein therapeutics. It describes the history, rationale, and state of the art of computational tools, such as Rosetta, that allow the design of rigidly structured peptide macrocycles. The emerging pipeline for designing peptide macrocycle drugs is described, including current challenges in designing permeable molecules that can emulate the chameleonic behavior of natural macrocycles. Prospects for reducing computational cost and improving accuracy with emerging computational technologies are also discussed. To embrace computational design of peptide macrocycle drugs, we must shift current attitudes regarding the role of computation in drug discovery, and move beyond Lipinski's rules. This technology has the potential to shift failures to earlier in silico stages of the drug discovery process, improving success rates in costly clinical trials. Given the available tools, now is the time for drug developers to incorporate peptide macrocycle design into drug discovery pipelines.


    Vikram K Mulligan. The emerging role of computational design in peptide macrocycle drug discovery. Expert opinion on drug discovery. 2020 Jul;15(7):833-852

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    PMID: 32345066

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