Disorders of the central nervous system (CNS) are responsible for diseases including neurodegenerative conditions (e.g. Parkinson’s Disease, Alzheimer’s disease), psychiatric conditions (e.g. schizophrenia, depression), neuropathic pain and more. The inherent complexity of these disorders, which often affect diverse neural circuits and signalling pathways makes CNS drug discovery uniquely challenging.
There are several key considerations associated with CNS drug discovery which are not often encountered in other disease target areas. In small molecule drug discovery, the presence of the blood brain barrier (BBB) can restrict the flow of drug to the brain, creating a major hurdle to be overcome. Mitigation of undesirable or toxic side effects must also be carefully considered. Animal models may not reflect the complexities of the diseases.
Our team has the experience needed to guide your projects through the challenges of CNS drug discovery. With wide-ranging backgrounds from Big Pharma, biotech, and academia, our team has a median drug discovery experience of 15 years with successes in advancing new chemical entities to the clinic. BioAscent has worked successfully on several CNS programmes, including fully integrated multi-FTE, hit to lead and lead optimisation programmes.
BioAscent offers an integrated platform for CNS drug discovery. Clients can benefit from access to chemistry, biosciences, and compound management services all on one site, together with rapid-turnaround ADME data provided by our trusted partners, resulting in faster design-make-test cycle times. We prioritise scientist-to-scientist communication between departments to ensure the best outcomes for your CNS projects. Read more about our integrated drug discovery projects.
Our scientists successfully worked with the customer to improve compound permeability and Kp,uu and establish a CNS-penetrant series for their oncology programme. BioAscent was responsible for all route design and synthesis, while our expert medicinal and computational chemistry team worked collaboratively with the customer to design the optimal compounds for the programme. Our hypothesis-driven approach:
Maintain tight control over the compound’s physicochemical properties
Design ideas scored against appropriate CNS design measures
Balance compound properties with key pharmacophoric elements to ensure potency and efficacy are maintained
Ligand-and structure-based in silico approaches used to aid selection of compounds for synthesis
A robust assay cascade was established by our biosciences department to support the design-make-test cycle, with comprehensive ADME and DMPK support provided by one of BioAscent’s trusted partners.
The chemistry team efficiently produced compounds for primary screens but also sufficient material for more advanced studies. The biosciences team developed additional assays to support further optimisation.
These studies resulted in compounds with improved brain-penetrant characteristics whilst maintaining good activity in cell-based assays.
For CNS-targeted drugs, BioAscent’s computational chemistry experts prioritise candidates with favourable CNS penetration using a combination of physicochemical property-based predictions and methods:
The CNS Multiparameter Optimisation (MPO) score assesses a molecule's physicochemical properties, providing a general indicator of its ability to cross cell membranes. A high CNS MPO score suggests a compound might have better passive diffusion across the blood-brain barrier (BBB).
The BBB score, composed of stepwise and polynomial piecewise functions, predicts BBB penetration based on five physicochemical descriptors.
The Free Energy of Solvation (E-sol), a method recently published by Schrodinger researchers, directly relates a compound's structure to its unbound brain-to-plasma partition coefficient (Kp,uu). Kp,uu is a key metric indicating how efficiently a drug crosses the BBB to reach its target in the brain.
The minimum solvent-accessible 3D polar surface area (Min SA 3D PSA) estimates the minimum polar surface area of a molecule accessible to solvent, which correlates with cell permeability. By minimising this surface area, one can potentially enhance a compound's ability to passively diffuse across the BBB.
By considering all or some of these metrics, our computational chemists can significantly enrich for compounds with better brain penetration potential, ultimately accelerating the discovery of effective CNS therapeutics.
Our computational and medicinal chemists work closely to prioritise target molecules that have the highest likelihood of achieving the required goals.
With broad expertise in CNS-focused medicinal chemistry, BioAscent’s chemistry team apply hypothesis-driven compound design to ensure we make the right molecules for your project.
Working in close partnership with our clients, we focus on modulating properties such as size, polar surface area, H-bond donor count and lipophilicity, to improve the likelihood of compounds crossing the BBB. As is the case for any medicinal chemistry programme, these properties must be carefully balanced to ensure that potency, selectivity, and efficacy for the target are maintained or enhanced.
BioAscent’s synthetic chemistry team is highly skilled in performing complex organic chemistry. Our chemists employ adaptive problem-solving to overcome synthetic challenges and frequently apply the latest methods and technologies to generate new chemical matter for customer programmes. In the CNS space, methods such as late-stage functionalisation and parallel library synthesis can afford rapid access to potent compounds with modified physicochemical properties. We have a dedicated analytical capability to ensure compounds prepared are of the highest purity and secure structural assignment.
Experts in bespoke assay development, our biosciences team can support CNS projects through the development of a robust in vitro assay cascade developing assays to support different stages of the drug discovery process from HTS campaigns to more detailed data-rich mechanism of action studies required further along the drug discovery path. Our team has a wealth of experience developing assays for target classes commonly encountered in CNS such as GPCRs and kinases.
At BioAscent, our protein production facility, state-of-the-art automation systems, and robust compound management capabilities position us as leaders in developing both target-based and phenotypic assays, which can be applied to discover new ligands for CNS targets using High Throughput Screening (HTS). We have our own libraries of compounds for lead identification, including a fragment library. We excel in transferring established assays or devising new ones, ensuring they meet rigorous specifications for HTS. Our meticulous quality control measures extend to the miniaturization of assays to 384- or 1536-well plates.
In addition to biochemical screens we have a wealth of experience in developing and applying a range of biophysical techniques (SPR, MST, DSF) to identify hits or characterise leads.
At BioAscent, we have developed assays to support CNS projects including:
Neurite outgrowth
cAMP
AlphaLisa
In-cell Western
We also hold a controlled substance licence, allowing us to handle compounds that fall into this category.
The studies above are underpinned by our compound management capabilities and expertise, which ensure seamless movement of synthesised compounds to testing irrespective of whether the tests are run in our own labs or elsewhere. Our data handling systems ensure secure and efficient transfer of data. Overseen by our project management process this ecosystem drives the speed and effectiveness of the design-make-test cycles leading to the best outcome, for you, the customer.
