RNA Dynamics Drug Discovery Platform
Biology and Drug Discovery Basics:
There are three key cellular molecules that ensure a properly functioning cell: DNA, RNA, and protein. DNA serves as a template to make RNA in a process called transcription while RNA serves as a template to produce protein in a process called translation (See Figure). Once made DNA, RNA and protein have functions that maintain cell health. Faulty DNA, RNA, or protein functions can cause and promote human disease. Drug discovery is the process of identifying drugs that favorably alter DNA, RNA, and/or protein function to alleviate human disease.
The Problem:
Small molecules that target RNA comprise one of the most successful drug classes of all time: antibiotics. Even with that success as precedence the technology has not existed to create a robust RNA-targeting drug discovery platform... until now.
Human genome related research indicates that up to 93% of the genome is transcribed into RNA yet fewer than 2% of those RNAs are translated into protein. Drug discovery efforts over the last fifty years have almost exclusively focused on the protein products of that small 2% of the RNA population; Nymirum aims to open up the other 93%.
Recent discoveries of diseases caused by dysfunctional human RNA, along with the explosion of potential RNA targets emerging from whole genome sequencing of disease causing microorganisms, require enabling technologies to identify drugs that alter RNA activity and thereby alleviate human disease. However, most RNA targets lack the enzymatic activity needed for high throughput screening and small molecule binding assays do not provide atomic level structural information needed to relate binding affinity to biological activity for robust structure activity relationship (SAR) studies. While computational methods that provide the desired structural information can in principle be implemented in a high throughput manner without experimental limitations, current docking protocols fail to take into account inherent RNA flexibility and the large conformational changes that take place when RNA binds small molecules. Thus, for systems with large degrees of conformational plasticity, such as RNA, they fail to adequately predict small molecule binding interactions. The Nymirum platform solves these problems and has been fully validated.
The Solution:
Nymirum's platform can begin as early as target selection and proceeds through chemical and biological lead optimization. Our success rates in finding drug-like compounds are dramatically higher and significantly faster than traditional methods.
The core of Nymirum's drug discovery platform is a novel approach that identifies specific atomic-level RNA conformers which co-exist in a dynamic ensemble. By determining the atomic coordinates of these conformations, Nymirum is able to delineate all possible RNA-small molecule interactions, the critical step in structure-based drug design. Using this insight, Nymirum directly targets the plasticity of RNA providing rapid identification of small molecules that can allosterically modulate RNA cellular function providing the necessary biological specificity.
There is an iterative feedback process between our chemistry, biology, and NMR steps. During our partnered projects we are able to incorporate our partners' domain expertise and requirements into the process.