Current and Future Challenges in Modern Drug Discovery.

Drug discovery is an expensive, time-consuming, and risky business. To avoid late-stage failure, learnings from past projects and the development of new approaches are crucial. New modalities and emerging new target spaces allow the exploration of unprecedented indications or to address so far undrugable targets. Late-stage attrition is usually attributed to the lack of efficacy or to compound-related safety issues. Efficacy has been shown to be related to a strong genetic link to human disease, a better understanding of the target biology, and the availability of biomarkers to bridge from animals to humans. Compound safety can be improved by ligand optimization, which is becoming increasingly demanding for difficult targets. Therefore, new strategies include the design of allosteric ligands, covalent binders, and other modalities. Design methods currently heavily rely on artificial intelligence and advanced computational methods such as free energy calculations and quantum chemistry. Especially for quantum chemical methods, a more detailed overview is given in this chapter.