Targeted and
Specialty Libraries

Macrocycle CNS Subset
Synthetic Macrocycles with Potential CNS Application

Topologically, macrocycles have the unique ability to span large surface areas while remaining conformationally restricted compared to acyclic molecules of equivalent molecular weight. Macrocyclization also reduces overall polarity and enhances membrane penetration compared to acyclic molecules of equivalent molecular weight. Taken together these attributes make macrocycles a powerful approach for any lead discovery program against challenging targets. However, for CNS drug discovery, macrocyclic leads are not typically thought of as attractive starting points as the TPSA and HBD count tends to be outside of what is considered an acceptable range for blood brain barrier penetration. By determining the number of internal hydrogen bonds a macrocyclic molecule makes in a solvent with a low dielectric constant and discounting the HBD count and TPSA (-20 Å per HBD) ChemBridge has identified a subset of more than 3,000 macrocyclic compounds from its Macrocycle Library predicted to have a high probability of good blood brain barrier penetration based on an MPO scoring approach.

View the Macrocycle CNS-Subset product sheet
View the Macrocycle CNS-Subset poster

Highlights
  • Subset of synthetic macrocycles with potential application for CNS drug discovery
  • Extensive conformational analysis performed to identify low energy macrocyclic conformations with internal hydrogen bonds
  • 3,000+ macrocycles available; custom select or purchase the full set
CNS Multiparameter Optimization (MPO) score

A fundamental challenge for the design of CNS penetrant drugs is the need to cross the BBB. An important observation for BBB permeable compounds is their physicochemical parameters form a smaller subset within the property space of oral drugs. To best define the physicochemical properties for CNS library design ChemBridge selected a weighted scoring approach first described by Verhoest and Wager et al in 2009 and more fully described in a 2010 article1 known as the CNS Multiparameter Optimization (MPO) score. The CNS MPO score is now a well-recognized algorithm in the CNS focused medicinal chemistry community. The algorithm uses a weighted scoring function assessing 6 key physicochemical properties (ClogP, ClogD, MW, TPSA, HBD, and pKa) for BBB penetration, CYP mediated metabolism and inhibition of dofetilide binding. The score is between 0-6 with scores ≥ 4.0 widely used as a cut-off to select compounds for hit finding in CNS therapeutic area drug discovery programs

A key factor in calculating the CNS MPO score for macrocycles was to predict the possibility of the formation of intramolecular hydrogen bonds in low energy conformations. These conformations are reflective of the macrocycles as it passes through the membrane. Once the internal hydrogen bonds are counted the MPO score is adjusted accordingly.2

Methodology

A detailed 3D conformational analysis of the initial 6,000 macrocycles from the ChemBridge Macrocycle Library was performed to examine the number of intramolecular hydrogen bonds. Data from the conformational analysis was used to adjust the HBD and tPSA values and resulting MPO score for each compound and identified a subset with an “adjusted MPO” score ≥ 4.0.

Analysis Process:

  1. Retain all macrocycles with CNS MPO ≥ 4.0 (these meet the MPO cutoff without need to form intramolecular hydrogen bonds)
  2. Remove all macrocycles with CNS MPO < 4.0 and without ability to achieve adjusted CNS MPO ≥ 4.0 with all HBD internally hydrated
  3. For remaining macrocycles with CNS MPO < 4.0 but with potential to form internal hydrogen bonds and achieve an adjusted CNS MPO ≥ 4.0, perform an extensive conformational search with molecular mechanics minimization, fast implicit vibrational analysis and short molecular dynamics simulation3
  4. Count maximum number of intramolecular hydrogen bonds predicted from conformational search (conformations analyzed were within 2.8 kcal/mol of minimum)
  5. Calculate the adjusted MPO score taking into account the predicted intramolecular hydrogen bonds; retain macrocycles with adjusted CNS MPO of ≥ 4.0
  6. Combine macrocycles from step 1 and 5 as CNS Subset (3,000+ macrocycles)

Figure 1: Macrocycle ID 14120758 has an MPO score of 3.0 when calculated using standard CNS MPO methodology based on 2D structure. Detailed 3D conformational analysis shows the macrocycle forms 3 internal hydrogen bonds in a low energy conformation (low energy conformations are defined within 2.8 kcal/mol of minimum). The CNS MPO score is adjusted to count only the solvent exposed hydrogen bond donors and TPSA reduced by 20Å per internal hydrogen bond.

Format
  • Download structures and custom select compounds from the Macrocycle CNS Subset SDfile
  • Compounds can be provided in 96-well and 384-well format
  • Amounts as low as 0.25 micromole (25ul of 10mM DMSO solution) available
  • Compounds are available as DMSO solutions or dry in micromole or mg amounts

For more information or a file of compound structures, please contact ChemBridge Sales.

References
  1. Wager TT, Hou X, Verhoest PR; Villalobos A. Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach to Enable Alignment of Druglike Properties. ACS Chem. Neurosci. 2010 Jun 16; 1(6): 435–449. PMID 22778837
  2. Hickey JL, Zaretsky S, St Denis MA, Kumar Chakka S, Morshed MM, Scully CC, Roughton AL, Yudin AK. Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds, J. Med. Chem. 2016, 59(11), 5368−5376 PMID 27120576
  3. Labute P, Williams C, Feher M, Sourial E, Schmidt JM. Flexible Alignment of Small Molecules. J. Med. Chem., 2001, 44(10), 1483–1490 PMID 11334559