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.
Carefully selected from the Life Chemicals HTS Compound Collection to meet the parameters optimized for high BBB-permeability (listed in the Table 1 and Fig. 1 below) is our CNS Focused Screening Library comprising over 30,300 structurally-diverse and potentially CNS-active screening compounds. This original Screening Compound Library is aimed at supporting CNS drug design projects and HTS efforts in search for novel neurotherapeutics.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
For a pre plated set based on this Screening Library, please explore our Pre-plated Focused Libraries.
Figure 1. Compound selection workflow for the Life Chemicals CNS Screening Library.
Compound Selection
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 the CNS unless they undergo active transport across the BBB.
In general, CNS-penetrant 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].
To select screening compounds for this CNS-focused screening set, the parameter calculations were performed with the SYBYL-X and ChemAxom JChem software. Then the CNS multiparameter optimization was applied. PAINS and toxicophore-containing compounds were removed by our in-house MedChem filters.
Table 1. Physicochemical parameters used for screening compound selection
| 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 |
Representative screening compounds with physicochemical parameters and MPO score favorable for BBB penetration for CNS-related drug-discovery
References
- Pardridge W. M. Blood-brain barrier delivery. Drug Discovery Today. 2007, 12 (1/2); 54–61.
- Pajouhesh H., Lenz G. R. Medicinal chemical properties of successful central nervous system drugs. NeuroRx., 2005, 2; 541–553.
- 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.
- 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.
- 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.
- 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.