Ophthalmic Drug Design

Palo Alto, CA —The ability to obtain high resolution crystal structures of proteins has shifted drug design into a new age. Computationally aided drug design is being increasingly used to expedite and simplify the drug discovery process. The ability to visualize the protein binding site allows researchers to design molecules that are complimentary to the target's structure, generating highly specific, novel inhibitors through a structure guided design approach.  

The Mahajan lab uses the Maestro interface within Schrodinger to obtain an in-depth view of the binding pocket and identify amino acid residues to make key interactions. Envisioned inhibitors can then be modeled and scored using Glide Docking to quantify the results. Top inhibitors can then be modified to further optimize protein-ligand interactions to generate lead-like compounds. 

These virtually-designed lead-like compounds are then synthesized in collaboration with Stanford’s Medicinal Chemistry Knowledge Center (MCKC) for biochemical and cellular testing.  

“The ability to visualize the interactions and binding of our small molecules with the protein target allows us to logically, thoughtfully, and rapidly generate novel compounds that are likely to be successful inhibitors,” explained postdoctoral fellow Dylan Parsons. “Coupled with the close collaboration between chemists, biologists, and surgeon-scientists, we hope to speed up the typically slow drug discovery process to arrive at therapeutic agents as fast as possible.” 

Using the lead-like compounds provided by the MCKC, Mahajan team members then study the ocular pharmacokinetics throughout the lead optimization process. Unlike typical drug targets, the eye represents a unique system in regard to the pharmacokinetics observed. Systemic administration often results in poor delivery of the drug to the eye, so injection into the eye is common. This circumvents the typical absorption, distribution, metabolism, and execration involved with systemic administration.

“Eye injections are routine in our Stanford retina clinics,” Mahajan said. “Topical anesthetic along with a microscopic needle make the five-minute procedure pain-free for patients.”

Mahajan added, “Building interdisciplinary teams for drug design allows us to execute unique pipelines that take advantage of our exceptional ability to deliver drugs directly to the target cells.”