Prevention and treatment of diseases: a small molecule discovery and development approach




Dalwani, Dhwanil A.


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This work examined the structure-activity relationship, and molecular mechanisms of different structural classes of small molecules at their target receptors. Three different systems were explored and each chapter is devoted to a single system. All three systems utilized similar experimental approaches, and practical application of the same core pharmacological principles. The first system involved the evaluation of the structure-activity space of small molecules acting on the α-like octopamine receptors from the barnacle Balanus improvisus (BiOctR) and the fruit fly Drosophila melanogaster (DmOctR). A number of molecules belonging to the imidazole and imidazole structural class were determined to have high potency for the BiOctR and the DmOctR. This information will be useful in designing new OctR ligands that are highly selective for the OctRs over their mammalian off-targets. Similarly, for the second system, the structure-activity space of different structural classes of sigma-1 receptor (S1R) ligands were evaluated. Four novel EPGN compounds with more than 100-fold selectivity for the S1R over the sigma-2 receptor were identified which were able to stimulate S1R-mediated BDNF secretion. Potential therapeutic applications of these compounds include the treatment of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. The third system involved the identification of receptor off-targets of efavirenz that may be responsible for efavirenz’s neuropsychiatric adverse events (NPAEs). In this study, multiple receptor targets of efavirenz belonging to the serotonin receptor family and the muscarinic receptor family of G protein-coupled receptors (GPCR) were identified, and its mechanism of action at these targets was established. The most prominent finding of this study was that efavirenz functioned as an inverse agonist, antagonist and an allosteric modulator, depending on off-the target receptor. Knowing which off-target receptors efavirenz interacts with may help to understand the molecular mechanisms responsible for efavirenz’s NPAEs. Overall, the insights gained regarding the mechanisms of action of small molecules will aid in the discovery and development of novel compounds, or an improved understanding of known compounds with established or potential therapeutic value.