CNS Screening Library

The incidence and significance of central nervous system diseases are increasing at an alarming rate all over the world. Although substantial research efforts have been applied to develop new CNS-active drugs, only a few CNS disorders are addressed satisfactorily, while the remaining ones pose significant clinical challenges. Blood-brain barrier (BBB) permeability is one of the most important limiting factors in the design and development of novel CNS-targeted pharmaceuticals for the treatment of neurological disorders.

It has been estimated that a molecule’s blood brain barrier penetration depends on its molecular weight (MW), charge, and lipophilicity. Moderately lipophilic drugs cross the BBB by passive diffusion, while polar molecules do not penetrate well into CNS unless they undergo active transport across the BBB.

In general, CNS-active molecules tend to be more lipophilic and less flexible (number of rotatable bonds < 8), to have fewer hydrogen-bond donors (< 3) and acceptors (< 7), reduced MW, fewer formal charges (particularly, negative charges) and lower polar surface area [1-6].  

The Life Chemicals CNS Screening Library comprises almost 9,900 structurally-diverse, potentially CNS-penetrant compounds, carefully selected from the proprietary HTS Compound Collection to meet the parameters listed in the table below. 

Properties Range
MW 150 – 400
ClogP 1.3 – 3.0
PSA ≤ 65 Å2
HbD ≤ 3
HbAc ≤ 6
RotB ≤ 6
Rings 1 – 5
Total H-bonding < 8
Carboxylic acid group ≤ 1
S atoms ≤ 2
Cl atoms ≤ 2
Basic Nitrogen ≤ 2
Quaternary nitrogen 0
MPO Score ≥ 4

The calculations were performed with the SYBYL-X and ChemAxom JChem software. CNS multiparameter optimization was applied. PAINS and toxicophore-containing compounds were removed by in-house medchem filters. All compounds are in stock. Compound cherry-picking and hit resupply are available. 

The Library is aimed to facilitate the CNS drug design projects and HTS efforts in the search for novel neurotherapeutics.  A preplated set based on this Screening Library is also offered. For more details, please, consult our Pre-plated Focused Libraries. Please, contact us at orders@lifechemicals.com for quotations and formatting options.

Compound selection workflow - Life Chemicals CNS Screening Library

Figure 1. Compound selection workflow for the Life Chemicals CNS Screening Library.

References

  1. Pardridge W. M. Blood-brain barrier delivery. Drug Discovery Today. 2007, 12 (1/2); 54–61.
  2. Pajouhesh H., Lenz G. R. Medicinal chemical properties of successful central nervous system drugs. NeuroRx., 2005, 2; 541–553.
  3. Vlieghe1 P., Khrestchatisky M. Medicinal chemistry-based approaches and nanotechnology-based systems to improve CNS drug targeting and delivery. Medicinal Research Reviews, 2012, 00; 1– 60.
  4. Ghose, A. K.; Herbertz, T.; Hudkins, R. L.; Dorsey, B. D.; Mallamo, J. P. Knowledge-based, central nervous system (CNS) lead selection and lead optimization for CNS drug discovery. ACS Chem. Neurosci., 2012, 3, 50−68.
  5. Wager, T. T., Hou, X., Verhoest, P. R., & Villalobos, A. Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties. ACS Chemical Neuroscience, 2010, 1(6), 435–449.
  6. Mao, F., Ni, W., Xu, X., Wang, H., Wang, J., Ji, M., & Li, J. Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs. Molecules, 2016, 21(1), 75.
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