Progress towards the broad use of non-peptide synthetic macrocycles in drug discovery

Abstract

We discuss progress towards addressing three key questions pertaining to the design of screening libraries of synthetic non-peptidic macrocycles (MCs) for drug discovery: What structural and physicochemical properties of MCs maximize the likelihood of achieving strong and specific binding to protein targets? What features render a protein target suitable for binding MCs, and can this information be used to identify suitable targets for inhibition by MCs? What properties of synthetic MCs confer good pharmaceutical properties, and particularly good aqueous solubility coupled with passive membrane permeability? We additionally discuss how the criteria that define a meaningful MC screening hit are linked to the size of the screening library and the synthetic methodology employed in its preparation.

A DNA‐Encoded Chemical Library Incorporating Elements of Natural Macrocycles

“…Macrocycle libraries to date are typically peptide-derived and have great side-chain diversity, [3] but far less backbone diversity.Recent work, however, suggests that the backbone is intimately involved in the binding of macrocycles to their targets. [1,5] Great strides have been made in understanding the properties of macrocycles that improve their prospects as drugs,d espite their seemingly unfavorable physicochemical properties.T he Whitty [4,6] and Kihlberg [7] groups have independently examined large collections of macrocycles to try and identify as et of rules for predicting oral bioavailability beyond the rule-of-five.Akey feature seems to be am acrocyclesability to minimize its polar surface area when exposed to nonpolar solvents.T his "chameleonic" property is likely the source of the ability of many macrocycles to maintain cell permeability despite their size.H owever,t hese datasets are based on approved drugs from naturesb ounty of macro-cycles.Abigger collection of macrocycles to screen and study would allow us to determine whether they are truly unusual in terms of cell permeability and protein binding,orwhether our current thinking is biased by the compound set offered by natural evolution. [1,5] Great strides have been made in understanding the properties of macrocycles that improve their prospects as drugs,d espite their seemingly unfavorable physicochemical properties.T he Whitty [4,6] and Kihlberg [7] groups have independently examined large collections of macrocycles to try and identify as et of rules for predicting oral bioavailability beyond the rule-of-five.Akey feature seems to be am acrocyclesability to minimize its polar surface area when exposed to nonpolar solvents.T his "chameleonic" property is likely the source of the ability of many macrocycles to maintain cell permeability despite their size.H owever,t hese datasets are based on approved drugs from naturesb ounty of macro-cycles.Abigger collection of macrocycles to screen and study would allow us to determine whether they are truly unusual in terms of cell permeability and protein binding,orwhether our current thinking is biased by the compound set offered by natural evolution.…”

“…[4] In fact, natural macrocycles as aclass are characterized by highly diverse backbones rather than side chains. [1,5] Great strides have been made in understanding the properties of macrocycles that improve their prospects as drugs,d espite their seemingly unfavorable physicochemical properties.T he Whitty [4,6] and Kihlberg [7] groups have independently examined large collections of macrocycles to try and identify as et of rules for predicting oral bioavailability beyond the rule-of-five.Akey feature seems to be am acrocyclesability to minimize its polar surface area when exposed to nonpolar solvents.T his "chameleonic" property is likely the source of the ability of many macrocycles to maintain cell permeability despite their size.H owever,t hese datasets are based on approved drugs from naturesb ounty of macro-cycles.Abigger collection of macrocycles to screen and study would allow us to determine whether they are truly unusual in terms of cell permeability and protein binding,orwhether our current thinking is biased by the compound set offered by natural evolution. In this vein, anumber of exciting methods, both biological [8] and chemical, [3] have recently been developed to create large collections of encoded macrocycles.I n particular,the Liu lab has created abackbone-diverse DNAencoded macrocycle library (DEML), [3a-c] while the Neri lab [3d] has reported ahighly side-chain-diverse DEML built on ac onstant peptide scaffold ( Figure 1A,B).…”

Formation of Water Channels in the Crystalline Hydrates of Macrocyclic Compounds

“…Unique cyclic shape and ability to carry different functional groups make macrocyclic compounds eligible for applications in the fields such as pharmaceuticals, [1,2] chromatography, [3,4] nanotechnology, [5,6] and gas sorption/separation. [7,8] For example, cyclodextrin,acyclic oligomer of glucose has provent ob e useful in pharmaceutical product development owing to higher water solubility and ability to form stable inclusion complexw ith drug molecules.…”

Eine DNA‐kodierte Molekülbibliothek mit Elementen natürlicher Makrocyclen

“…Makrocyclische Tr effer sind oft hochgradig optimiert und nur aufwändig synthetisierbar,i nsbesondere wegen ihrer Grçße und ihres Ursprungs als Naturstoffe.Dies bietet nur wenig Spielraum fürc hemische Anpassungen, um ihre Eigenschaften verbessern zu kçnnen. [1,5] Es wurden große Fortschritte beim Verständnis ihrer Eigenschaften erzielt, vor allem im Hinblick auf die Optimierung ihres Wirkstoffpotentials.D ie Forschungsgruppen um Whitty [4,6] und Kihlberg [7] haben unabhängig voneinander große Sammlungen von Makrocyclen untersucht und eine Reihe neuer,u msetzbarer Grundregeln zusammengestellt, um die orale Bioverfügbarkeit von Makrocyclen jenseits der Lipinski-Regeln voraussagen zu kçnnen. Aktuelle Arbeiten zeigen jedoch, dass das Grundgerüst eine essenzielle Rolle im Binden von Zielstrukturen spielt.…”

“…[4] Tatsächlich werden Makrocyclen nach ihren hçchst vielfältigen Grundstrukturen klassifiziert. [1,5] Es wurden große Fortschritte beim Verständnis ihrer Eigenschaften erzielt, vor allem im Hinblick auf die Optimierung ihres Wirkstoffpotentials.D ie Forschungsgruppen um Whitty [4,6] und Kihlberg [7] haben unabhängig voneinander große Sammlungen von Makrocyclen untersucht und eine Reihe neuer,u msetzbarer Grundregeln zusammengestellt, um die orale Bioverfügbarkeit von Makrocyclen jenseits der Lipinski Die moderne Wirkstoffforschung beginnt typischerweise mit dem Te sten verschiedenster Substanzbibliotheken gegen ein gewünschtes Ziel. Die Tr effer werden dann zu Leitstrukturen optimiert, die ihrerseits fürI n-vivo-Tests weiteroptimiert werden.…”