Structural and conformational determinants of macrocycle cell permeability

Abstract

Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.

Small Molecule Targeting of Specific BAF (mSWI/SNF) Complexes for HIV Latency Reversal

“…To ensure that the preference for 2-phenyl pyridine isn’t due to nonspecific interactions, we also looked at the 75 compounds in the initial compound library that contained the 2-phenyl pyridine moiety and confirmed that only the DOS macrolactams were hits. Substituting phenyl for 2-phenyl pyridine at R 2 increased the cLogP from 3.5 to 4.2, which in conjunction with a lowered efflux ratio, could indicate that the increased activity is due to improved cell permeability (Over et al, 2016). There were 26 compounds that contained the 2-phenyl pyridine at position R 2 and varying substituents at R 1 and all were hits to some degree in the primary screen.…”

Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules

“…48 Additional limitations for the number of rotatable bonds and polar surface area were subsequently introduced 49 . Multiple examples of orally bioavailable molecules violating rule-of-5 principles, especially including macrocycles 33, 50–54 , have led researchers including Kihlberg and co-workers to develop alternative, expanded guidelines (MW ≤ 1,000 Da, # of H-bond donors below 6; # of H-bond acceptors below 15, cLogP from -2 to 10, # of rotatable bonds below 20, polar surface area below 250 Å 2 ) that are especially relevant to macrocyclic molecules such as those in our DNA-templated libraries 33, 53–57 (Table 1). …”

Neue Methoden und Designprinzipien für zellgängige Peptide

“…[64][65][66] Prinzipien aus der medizinischen Chemie werden schon seit Jahrzehnten auf Peptide angewendet, einschließlich Versuchen zur Begrenzung der Molekülgrçße,der polaren Oberfläche und der Wasserstoffbrückendonoren. [64][65][66] Prinzipien aus der medizinischen Chemie werden schon seit Jahrzehnten auf Peptide angewendet, einschließlich Versuchen zur Begrenzung der Molekülgrçße,der polaren Oberfläche und der Wasserstoffbrückendonoren.…”

“…Lokey und Mitarbeiter identifizierten in diesen Studien dutzende Beispiele von cyclischen, N-methylierten Peptiden mit internen wasserstoffverbrückten Strukturen und stellten systematische Struktur-Aktivitäts-Beziehungen auf,d ie aufzeigen, welche Eigenschaften die passive Zellpenetration fçrdern. [64][65][66]137] Die Determinanten fürd ie passive Zellpenetration kleiner cyclischer Peptide sind relativ klar definiert, einige Fragen bleiben aber offen. [135] Außerdem wurde eine ungefähre untere Grenze fürd ie Hydrophobie passiv zellgängiger Moleküle bestimmt, die bei (logK hc/w ) > À2liegt, wobei K hc/w der experimentell ermittelte Kohlenwasserstoff/Wasser-Verteilungskoeffizient ist;d ie obere Grenze wird im Wesentlichen durch die Lçslichkeit bestimmt.…”