Using X-Ray Crystallography to Inform Small Molecule Drug Design
Abstract
This project involves organic synthesis, X-ray crystallography, and the design of small molecule drugs. The ultimate goal of this project is to better understand the forces that affect the conformation of small molecules in order to develop more effective cancer therapeutics. The key molecule in this project is in reminiscent of an indole-2-carboxamide, and past research has shown that these molecules have antitumor and apoptotic effects against a variety of cancer cells. The crystals of this molecule were orthorhombic in P212121 with unit cell dimensions a = 14.0111(1), b = 17.7521(1), c = 45.0224(3) and a unit cell volume of 11198.26(7) Å3 (Z = 5), which is unusual. Analyzing the geometry of this small molecule led to the understanding that the crystal system was modulated and possessed a long range superhelical structure along the b-axis. In contrast to many similar indole-2-carboxamide derivatives, this molecule did not assume a tight and folded three-dimensional shape. This is because the presence of the two carbonyl groups caused it to bind to the two adjacent amide protons in nearby molecules. Studies have shown that new indole-2-carboxyamide derivatives can serve as allosteric modulators with improved potency compared to the parent compounds. However, the unusual solid-state conformational preference of the indole-2-carboxamide small molecule examined in this research raises questions on how it will act on its targets. The solid-state conformation of this molecule is different than typical indole-2-carboxamide derivatives, and that can inform the design of future therapeutics in this class of anti-cancer drugs.
Faculty Sponsors
Dr. Russell Driver
Project Type
Event
Location
Alvin Sherman Library
Start Date
4-5-2023 12:00 PM
End Date
4-6-2023 4:00 PM
Using X-Ray Crystallography to Inform Small Molecule Drug Design
Alvin Sherman Library
This project involves organic synthesis, X-ray crystallography, and the design of small molecule drugs. The ultimate goal of this project is to better understand the forces that affect the conformation of small molecules in order to develop more effective cancer therapeutics. The key molecule in this project is in reminiscent of an indole-2-carboxamide, and past research has shown that these molecules have antitumor and apoptotic effects against a variety of cancer cells. The crystals of this molecule were orthorhombic in P212121 with unit cell dimensions a = 14.0111(1), b = 17.7521(1), c = 45.0224(3) and a unit cell volume of 11198.26(7) Å3 (Z = 5), which is unusual. Analyzing the geometry of this small molecule led to the understanding that the crystal system was modulated and possessed a long range superhelical structure along the b-axis. In contrast to many similar indole-2-carboxamide derivatives, this molecule did not assume a tight and folded three-dimensional shape. This is because the presence of the two carbonyl groups caused it to bind to the two adjacent amide protons in nearby molecules. Studies have shown that new indole-2-carboxyamide derivatives can serve as allosteric modulators with improved potency compared to the parent compounds. However, the unusual solid-state conformational preference of the indole-2-carboxamide small molecule examined in this research raises questions on how it will act on its targets. The solid-state conformation of this molecule is different than typical indole-2-carboxamide derivatives, and that can inform the design of future therapeutics in this class of anti-cancer drugs.
