RATIONAL DESIGN, SYNTHESIS, AND CHARACTERIZATION OF NOVEL mPGES-1 INHIBITORS AS NEXT GENERATION OF ANTI-INFLAMMATORY DRUGS

Author

Ziyuan Zhou, University of KentuckyFollow

Date Available

7-24-2019

Year of Publication

2017

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

Advisor

Dr. Chang-Guo Zhan

Abstract

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are currently widely used as fever and pain relief in patients with arthritis and other inflammatory symptoms. NSAIDs effect by inhibiting cyclooxygenase-1 (COX-1) and/or cyclooxygenase-2 (COX-2). COX isozymes (COXs) are key enzymes in the biosynthesis of prostaglandin H₂ (PGH₂) from arachidonic acid (AA). It is now clear that prostaglandin E₂ (PGE₂), one of the downstream products of PGH₂, is the main mediator in both chronic and acute inflammation. Microsomal prostaglandin E synthase (mPGES-1) is the terminal enzyme of COX-2 in the PGE₂ biosynthesis pathway. Different from other two constitutively expressed PGE₂ synthase (PGES), mPGES-2 and cPGES, mPGES-1 is induced by pro-inflammatory stimuli and responsible for the production of PGE₂ related to inflammation, fever and pain. For these reasons, selective inhibition of mPGES-1 is expected to suppress inflammation induced PGE₂ production and, therefore, will exert anti-inflammatory activity while avoid the side effects of COXs inhibitors, such as gastrointestinal (GI) toxicity, and cardiovascular events.

A combination of computational and experimental approaches was used to discovery mPGES-1 inhibitors with new scaffolds. The methods used include molecular docking, molecular dynamic simulation, molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculation, and in vitro activity assays. Our large-scale structure-based virtual screening was performed on compounds in the NCI libraries, containing a total of ~260,000 compounds. 7 compounds have been determined for their IC₅₀ values (about 300 nM to 8000 nM). What’s more, these new inhibitors of mPGES-1 identified from virtual screening did not shown significant inhibition against COX isozymes even at substantially high concentrations (e.g. 100 µM).

Rational methodology for drug design and organic synthesis were applied to generate three series of mPGES-1 inhibitors with different scaffolds. In total, about 200 compounds were synthesized and tested for their in vitro inhibition against human mPGES-1. Compounds with high potency against human mPGES-1 were further screened for their inhibition against mouse mPGES-1 and selectivity of human mPGES-1 over COXs. Several compounds were identified as submicromolar inhibitors against human mPGES-1 with high selectivity over COXs.

In general, we have successfully identified a library of compounds as potent mPGES-1 inhibitors without significant inhibition against COXs. Structure information and in vitro activity evaluation data generated from the virtual screening and the library of compounds will be used to guide future design and synthesis of the mPGES-1 inhibitors.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2017.270

Recommended Citation

Zhou, Ziyuan, "RATIONAL DESIGN, SYNTHESIS, AND CHARACTERIZATION OF NOVEL mPGES-1 INHIBITORS AS NEXT GENERATION OF ANTI-INFLAMMATORY DRUGS" (2017). Theses and Dissertations--Pharmacy. 75.
https://uknowledge.uky.edu/pharmacy_etds/75