(4dl) Improving Drug Safety and Efficacy through Classical and Quantum Simulations

Research Interests: Understanding molecular-level processes in the cells and body tissues is essential for ensuring the efficacy and safety of drugs and therapeutics, yet there remains a significant challenge. By delving into the intricate interactions between molecules and different chemical environments, we can uncover the underlying mechanisms of diseases and drug actions, paving the way for newer, safer, and more efficient drug design. My research interests focus on combining statistical mechanics theory with classical and quantum simulations to provide molecular-level insights into medical and biomolecular applications.

I have worked on investigating chemical stability (related to safety) and NMR relaxivity (related to efficacy) of MRI contrast agents, which are usually chelated structures of Gadolinium(III), a paramagnetic ion. Although Gadolinium-based contrast agents (GBCAs) are widely used in the clinical setting, there exist significant concerns over their safety due to bioaccumulation in the brain, bone, and kidneys of patients with normal renal function. Thus, the development of new MRI contrast agents remains a challenge due, in part, to a limited understanding of the influence of molecular structure on the chemical stability and NMR relaxation of chelated paramagnetic ions.

Despite the long history of MRI and NMR, the existing models to describe NMR relaxation assume severe simplifications, while the actual phenomena display a rich and complex behavior. In this context, I have developed a theoretical approach to better model and interpret NMR relaxation autocorrelation function using simple, physical models within a rigorous statistical mechanical development leading to “molecular modes of NMR relaxation.” These modes arise from a diffusion propagator whose evolution is described by a Fokker-Planck equation and assumes no adjustable parameters. Within classical molecular simulations, I have been able to show great agreement between the calculated NMR longitudinal relaxation rates (used in MRI) and experimental measurements for both Gadolinium(III)-aqua and chelated Gadolinium(III) complexes used in clinical MRI at human body temperature. The simulations also reveal the underlying “molecular modes of NMR relaxation” for these systems, providing important insights into the physics of NMR relaxation at a molecular level.

I have also investigated the chemical stability of GBCAs using Molecular Quasi-Chemical Theory (m-QCT), which allows the treatment of short-range interactions using high-level quantum chemistry and longer-range interactions using coarse-grained (classical atomistic or continuum) methods. For the short-range interactions, electron density functional theory (DFT) calculations were performed at the meta-GGA hybrid level of theory (B3LYP and M06 functionals) to obtain the Gibbs free energy of the isolated inner-shell cluster. Accounting for long-range interactions using coarse-grained models gives the Gibbs free energy of the ion in the medium of choice, usually water at physiological conditions. By determining the Gibbs free energy difference of the chelated/unchelated structures, it is possible to assess the equilibrium coefficient (or partition coefficient) of the chelation reaction, the amount of (toxic) free ions, and rigorously assess the thermodynamic stability of chelation and how this is influenced by different chelate chemistries and solution conditions.

Teaching Interests: My teaching philosophy is centered on progressivism ideas. I value the importance of discerning each student's unique context, strengths, deficiencies, and interests before the introduction of novel educational content.

I co-taught twice the class of Statistical Mechanics and Molecular Simulations for undergraduate students during my master’s studies. During my Ph.D., I was a teaching assistant (T.A.) for five classes: Numerical Methods (both undergraduate and graduate levels), Thermodynamics (both undergraduate and graduate levels), and Kinetics and Reactor Engineering (graduate level). I was twice assigned a special T.A. position (Rice Dean’s T.A.), a paid appointment in which I was given more teaching responsibilities than a regular T.A., and had to work very closely with the principal instructor. Moreover, I was recognized as one of the finalists of the Teaching Award for Student Support at the university level.