Research

Postdoctoral research

My research on the Chodera Lab focuses on antiviral discovery for targets of pandemic potential, utilizing physics-based and AI-driven methods. Working with the AI-driven Structure-enabled Antiviral Platform (ASAP), I aim to advance methodologies and computational chemistry pipelines to facilitate structure based design and assessment of antivirals of broad spectrum.

Designing broad spectrum antivirals for pandemic preparedness

The rapid emergence of viruses with pandemic and epidemic potential represent a continuous threat for public health worldwide. With the typical drug discovery pipeline taking an average of 6 years to reach the pre-clinical stage, we need to develop strategies to design antivirals with broad spectrum activity that can provide treatment to a breadth of viral family members and variants of concern of existing circulating viruses that could cause human infections in the future.

I present a computational pipeline that will aid in the identification and assessment of broad-spectrum inhibitors across viral family members for a given target, or across mutant variants of a target of interest. Given a PDB crystal structure of a protein-ligand complex of interest, my pipeline consists of three steps:

An automated search for related viral sequences to a specified target construct by performing a BLAST search on the reference complex.
Structure prediction of sequences of interest with AlphaFold2, on sequences previously filtered to match a stablished criteria.
Ligand transfer and pose prediction, from the reference complex into the prected apo-proteins.
Refinement of predicted poses, by performing a MD minimization or short simulation to reduce unfavorable interactions.
Docking of new compounds, based on the refined poses
Evaluating breadth of antiviral activity via scoring of posed protein-ligand complexes.

I applied this workflow to the prediction of antivirals of broad spectrum for the coronavirus family. A preprint detailing this work is included below:

Prediction_of_antiviral_spectrum_breadth_for_viruses_of_pandemic_potential.pdf

PhD Research

Excitons in organic semiconductors

Organic semiconductors, commonly used in materials such as solar cells, transistors (TFTs) and light-emitting devices (OLEDs), promise to be a cost-effective and environmentally friendly alternative to traditional electronics, due to their flexibility, temperature stability, and the abundance of their foundational materials.

Central to organic semiconductors are photoactive materials such as chromophores or dyes. An extensive 𝜋-conjugated system—alternated single and double bonds—allows these molecules to absorb light in the visible spectrum (400–700 nm), due to absorption of light in low-lying electronic states. Upon photoexcitation, e.g., by a photon, an electron is created in the lowest unoccupied molecular orbital and a “hole” in the highest occupied MO (HOMO). When multiple chromophores are closely interacting with each other, a "molecular circuit" can be created from the delocalization of an electron-hole pair (an exciton) across the molecules in the network.

The dynamics of excitons enable energy and information transfer within molecular networks, positioning chromophore assemblies as ideal candidates for a number of technologies such as solar energy conversion, nanoelectronics, and quantum computing.

High-throughput screening of excitons in organic circuits attached to DNA nanostructures

During my PhD, I investigated DNA as a scaffolding media to control the photophysics of chromophore aggregates,by attaching these molecules to the DNA at specific distances an orientations.

Interactions between chromophores in molecular networks originate from the interplay between short and long-range interactions. For instance, long-range interactions regulate exciton delocalization and transfer amidst neighboring chromophores, whereas short-range interactions promote exciton evolution into charge-separated states. The latter emerge from the overlap of neighboring molecular orbitals and are particularly sensitive to even minor shifts in chromophore orientation.

The magnitude of the long-range excitonic coupling interaction (V_exc) and the short-range charge transfer interactions (V_CT) varies according to the relative geometry of the molecules.

I developed a high-throughput computational framework aimed at screening chromophore scaffold configurations with specific optoelectronic properties. Harnessing the strengths of MD combined with quantum mechanics, this software allows us to evaluate different configurations of chromophores scaffolded in DNA, capturing and analyzing geometric patterns and associating them with changes in the long- and short-range interactions.

The workflow consists of four steps: 1) Sampling the dimer positions within a full-length DNA construct. 2) Conducting MD simulations of these dimer samples in DNA. 3) Employing quantum mechanics to analyze trajectory statistics. 4) Undertaking synthesis and spectroscopic characterization of promising candidates.

Page updated

Google Sites

Report abuse