Abstract
Microsomal prostaglandin E2 synthase-1 (mPGES-1) is known as an ideal target for next generation of anti-inflammatory drugs without the side effects of currently available anti-inflammatory drugs. However, there has been no clinically promising mPGES-1 inhibitor identified through traditional drug discovery and development route. Here we report a new approach, called DREAM-in-CDM (Drug Repurposing Effort Applying Integrated Modeling-in vitro/vivo-Clinical Data Mining), to identify an FDA-approved drug suitable for use as an effective analgesic targeting mPGES-1. The DREAM-in-CDM approach consists of three steps: computational screening of FDA-approved drugs; in vitro and/or in vivo assays; and clinical data mining. By using the DREAM-in-CDM approach, lapatinib has been identified as a promising mPGES-1 inhibitor which may have significant anti-inflammatory effects to relieve various forms of pain and possibly treat various inflammation conditions involved in other inflammation-related diseases such as the lung inflammation caused by the newly identified COVID-19. We anticipate that the DREAM-in-CDM approach will be used to repurpose FDA-approved drugs for various new therapeutic indications associated with new targets.
Highlights
A variety of human diseases, such as the newly identified coronavirus disease 2019 (COVID-19), various forms of pain, cardiovascular diseases, neurodegenerative diseases, and cancers[1,2,3], involve serious inflammation conditions without a truly effective and safe anti-inflammatory drug to suppress
The DREAM-in-CDM approach consists of three steps: (1) computational modeling to predict which FDA-approved drugs may favorably bind with the desirable drug target; (2) in vitro and/or in vivo assays to validate the computational predictions; (3) clinical data mining to confirm the efficacy associated with the required clinical end points for the new therapeutic indication
We tested the binding of the 15 drugs with the high-resolution crystal structure (4AL0 with a high resolution at 1.2 Å) of Microsomal prostaglandin E2 synthase-1 (mPGES-1) in which co-factor glutathione (GSH) was removed from the binding site before molecular docking, confirming that these drugs can bind to the GSH-binding site of the crystal structure
Summary
A variety of human diseases, such as the newly identified coronavirus disease 2019 (COVID-19), various forms of pain, cardiovascular diseases, neurodegenerative diseases, and cancers[1,2,3], involve serious inflammation conditions without a truly effective and safe anti-inflammatory drug to suppress. The traditional nonsteroidal anti-inflammatory drugs (NSAIDs) either weakly and non-selectively inhibit both COX-1 and COX-2 or potently and selectively inhibit COX-2 All these traditional drugs have a number of serious adverse side effects, including the increased risk of fatal heart attack or stroke and stomach or intestinal bleeding etc., because the COX-1/2 inhibition blocks the synthesis of all of the other prostaglandins (PGs), including PGI2, PGD2, PGF2α, and TXA2 that are required physiologically, synthesized from PGH27. We report a new approach, called DREAM-in-CDM (Drug Repurposing Effort Applying Integrated Modeling-in vitro/vivo-Clinical Data Mining), to identify an FDA-approved drug suitable for use as an effective analgesic targeting mPGES-1. By using the DREAM-in-CDM approach, multiple FDA-approved drugs (that can be used orally), including lapatinib, have been identified as truly promising mPGES-1 inhibitors that may be repurposed to treat various inflammation-related diseases
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