Small Molecule Complementarity As A Source of Novel Pharmaceutical Agents and Combination Therapies

Abstract

Many examples of specific binding between small molecules are known that are associated with modified physiological and pharmacological activities. Conversely, the antagonism or synergism of small molecules is often correlated with specific binding between the molecules. It follows that small molecule binding can be used as a relatively quick, easy, and specific screen for functionally useful drug actions and interactions. These actions and interactions may manifest themselves as functional antagonisms; binding may correlate with enhancement or synergism; the formation of some complexes may yield clues about how drugs may be targeted to specific cell types in vivo and provide leads for the development of antidotes for drug overdoses or poisoning; the binding of one molecule to another may mimic receptor binding; and complexation may provide novel ways of protecting and delivering drugs. Relevant examples from each type of application are reviewed involving peptide-peptide interactions; peptide-aromatic compound interactions; aromatic-aromatic compound interactions; vitamin-aromatic compound interactions; and polycyclic compound interactions. We argue that screening for molecular complementarity of small molecules turns ligands such as neurotransmitters and their metabolites, hormones, and drugs themselves, into direct targets of drug development that can augment screening new compounds for activity against receptors and second messenger systems. We believe that the small molecule complementarity approach is novel, fruitful and under-utilized.

A Simple Three-Step Method for Design and Affinity Testing of New Antisense Peptides: An Example of Erythropoietin

“…The current accent in pharmacological research is modulation of protein–protein interactions, and the use of complementary peptides provides insight in such systems [49,50]. The method may be easily adapted for high-throughput screening, especially in the context of microscale thermophoresis equipment developed for this purpose [42].…”

Glutathione and Glutathione-Like Sequences of Opioid and Aminergic Receptors Bind Ascorbic Acid, Adrenergic and Opioid Drugs Mediating Antioxidant Function: Relevance for Anesthesia and Abuse

“…Three additional observations also serve to link antioxidant activity, opioids and adrenergic compounds. First, ascorbic acid binds directly to adrenergic compounds forming a stable complex that greatly retards oxidation of the amines [ 80 , 81 , 82 , 83 , 84 ]. Next, ascorbic acid may also serve to protect the disulfide bonds that stabilize the highly active forms of adrenergic and opioid receptors [ 85 ].…”

Mutual Enhancement of Opioid and Adrenergic Receptors by Combinations of Opioids and Adrenergic Ligands Is Reflected in Molecular Complementarity of Ligands: Drug Development Possibilities

“…Receptors for molecularly complementary ligands evolve complementary functions. For example, a homocomplementary molecule may evolve into a ligand–receptor pair, or heterocomplementary molecules may evolve so that one becomes the ligand and the other the receptor.As a result of principles 1–5, compounds that are molecularly complementary will alter each other’s physiological activity, and conversely, when compounds alter each other’s physiological activity, they will be found to be molecularly complementary [77]. Finally, there is a molecular paleontology within modern proteins that provides clues to how complementary modules were selected for and employed in any given set of receptors and transporters [70,74].…”