Date Approved


Embargo Period


Document Type


Degree Name

MS Pharmaceutical Sciences


Chemistry and Biochemistry


College of Science & Mathematics

First Advisor

Wu, Chun

Second Advisor

Jonnalagadda, Subash

Third Advisor

Ramanujachary, Kandalam




Pharmacy and Pharmaceutical Sciences


This thesis comprises of three computer aided drug design studies utilizing molecular docking and molecular dynamic simulations: (i) a lead optimization study virtually screening an initial library of ~120000 lead compounds targeting fungal leucyl tRNA synthetase, (ii) an exploratory study to understand the binding pathway of BRACO19 to a parallel telomeric DNA G-quadruplex by MD simulations and compare with experimentally solved X-ray crystal structure (iii) a comparative study to understand the lack of selectivity of BRACO19 to various topologies of human telomeric DNA G-quadruplex over DNA duplex.

The first chapter provides the background information required to understand the molecular docking studies and molecular dynamics simulation (MD) studies conducted and discussed in this thesis. This introductory chapter is organized as follows: the first section is an introduction to molecular recognition in protein-ligand interactions, the second section introduces computer-aided drug design, the third section introduces homology modelling, the fourth section discusses molecular docking and virtual screening, the fifth section introduces methods for binding affinity prediction and the sixth section explains MD simulations.

The second chapter of this thesis proposes a library of compounds with enhanced activity compared to the parent molecule it had been modified from. Tavaborole, the recently approved topological anti-fungal drug, inhibits leucyl tRNA synthetase by irreversible covalent bonding and hinders protein synthesis. The benzo-boroxole pharmacophore of tavaborole is responsible for its unique activity. This study theoretically proposes molecules with improved anti-fungal affinity.

The third chapter of this thesis explores the binding pathway of anti-cancer drug, BRACO19 and human telomeric DNA G-quadruplex. G-quadruplex specific ligands that stabilizes the G-quadruplex, have great potential to be developed as anticancer agents. A free human telomeric DNA G-quadruplex and an unbound BRACO19 are simulated and the resulting structure is then compared with an experimentally solved X-ray structure of human telomeric G-quadruplex with a bound BRACO19 intercalated within the G-quadruplex. Three binding modes have been identified: top end stacking, bottom intercalation and groove binding. Bottom intercalation mode (51% of the population) is identical to the binding pose in the X-ray solved crystal structure.

The fourth chapter of this thesis compares different topological folds of human telomeric DNA G-quadruplexes (parallel, antiparallel and hybrid) that have been experimentally solved using molecular dynamic simulation to understand the 62-fold preferential selectivity of BRACO19 towards human telomeric DNA G-quadruplex over DNA duplex. Groove binding mode was found to be the most stable binding mode for the duplex and top stacking mode for the G-quadruplexes. The non-existential binding selectivity of BRACO19 can be accounted to the similar groove binding to both the duplex and the G-quadruplex. For that reason, a modification should be induced such that this prospective ligand destabilizes binding to the duplex but stabilizes the G-quadruplex binding.