Applying Molecular Modeling to Design Substituted Pyrimidines as Potential Anti-Inflammatory Drugs
Additional Funding Sources
This project is supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award No. R25GM123927.
Presentation Date
7-2020
Abstract
Inflammation plays an integral role in the immune response as it protects against harmful stimuli such as parasitic infections, damaged cells, and toxic substances during an acute inflammatory response. However, unchecked activation of an acute inflammatory response shows an increased expression of pro-inflammatory cytokines (ICs) which contribute to a variety of chronic inflammatory diseases such as inflammatory bowel disease, tuberculosis, and various cancer types. This presents a need for the development of anti-inflammatory drugs as novel therapeutics to treat and inhibit ICs. We hypothesize that small molecule inhibitors (SMI) with optimal binding and drug-like properties can be discovered by utilizing molecular modeling. Initially, 2,4-disubstituted pyrimidines were rationally designed as potential inhibitors based on the structure of the IC and inhibitors discovered in our lab. Using molecular modeling software, binding energy and pose in potential active sites have been predicted for each designed compound. Further, drug-likeness, lipophilicity, and medicinal chemistry properties have been predicted using SwissADME. Several potential inhibitors held high binding energies of {-8.4, -8.1, -8.3} and possessed high drug-likeness and satisfactory pose in potential active sites as was observed by our lab. This offers an opportunity to develop targeted therapeutics to treat numerous inflammatory diseases.
Applying Molecular Modeling to Design Substituted Pyrimidines as Potential Anti-Inflammatory Drugs
Inflammation plays an integral role in the immune response as it protects against harmful stimuli such as parasitic infections, damaged cells, and toxic substances during an acute inflammatory response. However, unchecked activation of an acute inflammatory response shows an increased expression of pro-inflammatory cytokines (ICs) which contribute to a variety of chronic inflammatory diseases such as inflammatory bowel disease, tuberculosis, and various cancer types. This presents a need for the development of anti-inflammatory drugs as novel therapeutics to treat and inhibit ICs. We hypothesize that small molecule inhibitors (SMI) with optimal binding and drug-like properties can be discovered by utilizing molecular modeling. Initially, 2,4-disubstituted pyrimidines were rationally designed as potential inhibitors based on the structure of the IC and inhibitors discovered in our lab. Using molecular modeling software, binding energy and pose in potential active sites have been predicted for each designed compound. Further, drug-likeness, lipophilicity, and medicinal chemistry properties have been predicted using SwissADME. Several potential inhibitors held high binding energies of {-8.4, -8.1, -8.3} and possessed high drug-likeness and satisfactory pose in potential active sites as was observed by our lab. This offers an opportunity to develop targeted therapeutics to treat numerous inflammatory diseases.