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Computer-Aided Drug Design Modeling & Simulation Lab

Modeling & Simulation Lab


Membrane-facilitated ligand access and binding to

G Protein-coupled receptors (GPCRs) and Ligand-Gated Ion Channels


Membrane proteins constitute approximately one-third of all proteins expressed in humans and are involved in numerous fundamental cellular processes. Strikingly, G protein-coupled receptors (GPCRs) and ion channels, together, constitute 31% of all human therapeutic targets through which >50% of the marketed small-molecule drugs exert their pharmacological effects, underlining their significance.  Cell membranes have been known to serve as essential structural media for proper localization, structure, and function of these protein targets. However, a growing body of evidence shows that membrane lipids play roles that are even more sophisticated. Remarkably, several crystal structures of GPCRs and ligand-gated ion channels bound to their ligands offer unprecedented details on the existence of allosteric binding sites at lipid-transmembrane helix interfaces that can be accessed only via lipid-mediated paths. In addition, recent biophysical and computational studies (including data from our lab) reveal that lipophilic and amphiphilic ligands gain access to their protein targets by first partitioning into the surrounding membrane and then undergoing two-dimensional lateral diffusion through the membrane. The structural organization and constraints of the bilayer, including lipid composition, appear to play critical roles in directing ligands to a specific depth within the bilayer, and in “pre-organizing” them in an optimal orientation and conformation to facilitate receptor binding. Despite the clear participation of membrane lipids in molecular recognition processes, the mechanistic details of lipid involvement in the binding of drugs to integral membrane proteins remain poorly understood. There is a critical gap in the fundamental knowledge of how interactions among these species affect access, binding kinetics, and affinities of drugs to lipid-exposed transmembrane sites. The long-term goal of our research program is to contribute to this body of knowledge using advanced modeling and simulation techniques.

The ongoing research projects are supported by the following grants from the National Institutes of Health.

Active Grants

NIH/NIGMS – R15 GM131293-01 (9/20/2018 – 08/31/2021)
Specifics of “Non-Specific Membrane Interactions” of Drugs: An Integrated Approach for Understanding Structure-Membrane Interaction Relationships.
Role: PI

NIH/NINDS – R41 NS107099-01 (09/01/2018 – 08/31/2019)
In Silico Identification of Novel GHB Receptor Ligands for SSADH Deficiency, a Disorder of GABA Metabolism.
Role: PI, in collaboration with Speragen Inc.

NIH/NIAID – R01 AI083387-07A1 (08/01/2018 – 07/31/2022)
Molecular and cellular mechanism regulating innate immunity and inflammation during pattern recognition receptor activation and respiratory virus infection.
Role: Co-I, in collaboration with Dr. Santanu Bose (PI)


Ila Srivastava, Senthil Natesan, Justin Chen, Christopher Szlenk, and Jeevan GC (from left to right)