Tag: structure-based design

SkelGen – A Newly Available Tool for Computational Drug Design

drug designWith the rapidly growing body of biostructural information, structure-based drug design has increased in importance and a variety of computational methods have found a place in the drug discovery toolkit.

The de novo design program, SkelGen, was developed by De Novo Pharmaceuticals based on research begun in the Department of Pharmacology at the University of Cambridge. SkelGen constructs candidate ligands by assembling small molecular fragments within a protein target such as an enzyme or receptor (usually derived from X-ray crystal data). When growing a ligand, SkelGen uses information coded in the fragments and within its algorithm to favour synthetically tractable molecules. SkelGen is able to explore around one trillion low molecular weight, drug-like molecules using a default set of 1600 fragments. Since the accessible chemical space is so large, the majority of designed molecules are novel and patentable.

Whilst SkelGen can be run with minimal input, it also permits extensive control by the end-user, allowing the scientist to incorporate prior knowledge and insights into the drug design process. As well as completely de novo design, molecule generation can also be started from a user-defined fragment (for example, a low-affinity molecule identified by fragment-screening). SkelGen can also be used for scaffold hopping (chemotype switching) and focused library design.

Until recently SkelGen was only accessible through collaborations with De Novo Pharmaceuticals but is now available under both academic and commercial licenses. With these new licensing models, SkelGen can be a cost-effective (and accessible) tool for all scientists engaged in drug design. If you would like to find out more about SkelGen, please contact us.

Rational Design of New Type II Kinase Inhibitor

Crystal structure of sorafenib complexed with B-RAF, PDB ID=1UWH
Crystal structure of sorafenib complexed with B-RAF, PDB ID=1UWH
Protein kinases play important roles in regulating most cellular processes and are commonly activated in cancer cells. A number of kinase inhibitors – including antibodies and small molecules –have already been approved for the treatment of cancer and many others are currently being tested. The majority of kinase inhibitors developed so far are ATP mimetics identified by high-throughput screening of catalytic kinase domains at low ATP concentration. Such compounds – so-called type I inhibitors – may lack specificity for individual kinases and/or be less effective when ATP concentrations are high. Crystal structures have revealed that some compounds – the type II inhibitors – occupy an allosteric site accessible only in the inactive conformation of the kinase and researchers at the Moores Cancer Center at the University of California have now designed selective type II inhibitors of PDGFRβ (important for pericyte recruitment) and B-RAF (important for endothelial cell survival).
compound 6
Compound 6

Using the X-ray crystallographic structure of the type II inhibitor, sorafenib, bound to B-RAF, the team designed a small library of compounds based on a constrained amino-triazole scaffold predicted to stabilise kinases in the inactive state. The compounds were then tested for antivascular activity in both cell-based models and a zebrafish embryogenesis model. Compound 6 was found to inhibit both PDGFRβ and B-RAF cellular signalling – which produces a synergistic effect on tumour growth – but to have no effect on a variety of other cellular targets. The compound showed antiangiogenic activity in both zebrafish and murine models of angiogenesis and was also shown to suppress murine orthotopic tumors in both the kidney and pancreas.

The study is published in the Proceedings of the National Academy of Sciences.