The allure of targets for novel drugs

Abstract

The challenges of bringing new medicines to patients have been extensively discussed and debated, including consideration of the contribution that academic laboratories can make. At the University of Strathclyde, drug discovery has been a continuing focal activity since the 1960s, and in the past 30 years, the author has led or contributed to many projects of different character and for diverse diseases. A feature common to these projects is the extension of concepts of molecular and biological targets in drug discovery research. In mechanistic terms, these have included compounds that are activators and not inhibitors, and in particular multitargeted compounds. With respect to relevance to disease, schizophrenia, pulmonary disfunction, autoimmune, and infectious disease are most relevant. These projects are discussed in the context of classical medicinal chemistry and more recent concepts in and approaches to drug discovery.

Fig. 1. Multitargeted CNS active drugs.

Fig. 2. Structural relationships between the focal natural cofactor, tetrahydrofolate, and fused pyrimidines with various in vivo activities.

Fig. 3. Location of blocked dihdydropterin 7 in the active site of eNOS as determined by X-ray crystallography. Reproduced from Biochemistry, 2014, 53, 4216.

Fig. 4. Location of pyrrolopyrimidine inhibitors (green) at the active site of PTR1 adjacent to the reducing cofactor, NADPH (red). Reproduced from J. Med. Chem., 2014, 57, 6479.

Fig. 5. Pyrrolopyrimidines with antiparasitic activity. Seed compound (10 top) and four derivatives (11–14) that substantially cleared infection.

Fig. 6. Pirfenidone 15, its quinone methide formed by oxidation in vivo, and its interaction with thiols in peptides and proteins.

Fig. 7. Schematic of model of action of 16. 16 downregulates MyD88 expression and hence induces a partial uncoupling of TLR/IL-1R from NF-κB activation and consequent pro-inflammatory cytokine production. Reproduced from J. Med. Chem., 2013, 56, 9982.

Fig. 8. Model of SMAs' action in CIA: 12b = 17 protection predominantly reflects activation of NRF2 signaling to counteract MyD88-integrated inflammasome mediated IL-1β production. 11a = 17 preferentially targets MyD88-driven induction of the IL-17 inflammatory axis. Reproduced from J. Autoimmunity, 2015, 60, 59.

Fig. 9. Possible mechanism for the interaction of 17 with Keap (RSH).

Colin Suckling