Technology

Target identification and validation

Traditionally, drugs originated from an extract (i.e. plants) containing an active substance or similar. These drugs showed the desired effect in humans although the target molecules in the body and mode of action often remained unknown. Today this is turned up-side down. The fundament of a modern drug discovery program is the target molecules, and one seeks to identify novel compounds which binds to and modulates the target in a wanted manner. Proteins that are potential targets for male fertility are being thoroughly tested at Spermatech through biological and biochemical testing in the laboratory. This testing includes mice that have the target completely removed from their body (knock-out mice).

Structure biology

Structure biology has become a crucial part of modern drug discovery. Spermatech builds a model depicting the molecular surface of targets by performing protein crystallography. A precise picture showing protrusions, cavities and charges at the surface of a target is important since drugs need to fit to their target molecules like a key in a keyhole. At Spermatech, structure biology is an integrated part of the whole pipeline of early drug discovery.

Virtual screening (VS)

A molecular picture of our targets enables us to perform a screen for potential drugs by using computers and advanced algorithms (in silico screening). Such screens can give good starting blocks for further development in the laboratory and show a bias against a specific class of chemicals that could become a male contraceptive. We have performed a VS where we have screened millions of compounds in a computer. Promising hits were purchased and introduced to our biological assay (see below).

Assay development

When a target is validated one needs to identify a unique feature of the target that can be scored for in a test set-up. In biology such a set-up is called an assay. In general, an assay consists of a unique characteristic of the target that can be tested towards positive and negative control conditions. In addition, an assay suitable for drug discovery needs to be extremely robust, scalable (miniaturization) and tolerate robotic handling. Several assays involving living human sperm cells have been developed in Spermatech’s laboratories. The development of a successful assay is a well known bottleneck in the early phase of drug discovery, and our achievements in assay development have been critical for our future work.

High throughput screening (HTS)

A drug discovery project is ready to start searching for active chemical substances (compounds) when a validated target and robust assay is established. Today the preferred route is usually a kind of high throughput screening (HTS). In most cases HTS involves robotic handling and compound libraries consisting of several hundreds of thousands of molecules. These compounds are pre-selected to be drug-like molecules (i.e. known toxic compounds are left out) and should ideally represents a maximum of theoretical chemical space by a minimum of compounds. Spermatech has performed a HTS in collaboration with Evotec AG where we have used our assay and tested thousands of compounds for effect on our targets. The result of a successful HTS campaign is a few hit compounds or hit series of compounds.

Hit- and lead optimization

Hits need to be optimized for properties like potency, uptake by cells and organisms, toxicity and such. This is achieved by systematically changing chemical side groups of the hits by medicinal chemistry. Here, new chemical molecules are produced and put back into protein crystallography and assays to check for improved potency and decreased side effects. Optimized compounds are taken further until they reach the criteria for a lead and clinical candidate compound. In this way drug discovery is a highly iterative process where modified compounds cycles the assays numerous times. Improved compounds are the basis for further improvement, while the rest is discarded. Promising compounds are also introduced into animal models for more physiological testing as the project moves along our drug discovery pipeline.