Blog 1: Combining Docking, Molecular Dynamics Simulation, and Free Energy Calculation to Improve the Accuracy of Virtual Screening of Anticancer Drug Candidates Against Human Telomeric G-quadruplex DNA

In cancer research, the human telomeric G-quadruplex (G4) is a target of great interest and potential for anticancer drugs. At the ends of chromosomes in typical cells, the telomere is a region of repetitive nucleotide sequences that protect chromosomes from degradation and are cleaved little by little after each cell replication. This shortening of the telomere eventually leads to apoptosis (cell death), thus preventing the replication of critically shortened DNA. In the case of cancer, however, this programmed cell death does not occur due to the continuous activity of telomerase which facilitates the maintenance of the telomere lengths. Consequently, cancer cells continue to replicate without degradation and the malignant phenotype is retained. Previous research has shown that targeting the human telomeric G4 in telomeric DNA inhibits telomerase, effectively disrupting this process and disrupting telomere maintenance.

Thus, under the guidance and leadership of Professor Nanjie Deng, the purpose of this research project is to collaboratively improve computational screening of anti-cancer drug candidates binding human telomeric G4. In particular, this entails elucidating the ligand selectivity of protoberberines which have been previously studied to bind to human telomeric G4. Using docking, molecular dynamics simulation, and free energy calculation, we aim to determine which drug molecules have the highest chances of binding success. Final results will be presented at the American Chemical Society national meeting. 

Molecular docking is the process of predicting ligand conformation and orientation within a targeted binding site. Docking aims to find the ideal interaction energy between a specific receptor and ligand in order to create an ideal, stable resulting compound. Within the docking software, one can compare interaction energies of different forms/poses by using the software’s scoring function. For each possible pose, considering all conformational degrees of freedom, the scoring function gives a value that helps the researcher evaluate its affinity. We can increase efficiency by keeping the receptor rigid while keeping the ligand flexible; as a result, possible poses are more limited, and researchers have a narrowed down array of positions to evaluate. In general, this leads to researchers considering the binding energy values among other factors (e.g., enthalpy and entropy). Docking requires a rigorous amount of detail and specificity, however, thus this process can prove to be challenging. My particular role in our research lies in conducting molecular dynamics simulation calculations in order to better observe and analyze binding for data collection.

With our research, we aim to contribute to the worldwide effort of discovering newer and more effective cures for cancer.

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