Obesity-related diacylglycerol acyltransferase (DGAT1) inhibition is supported by morpholino-pyrimidine and pyrimidino-oxazine derivatives, showing stable binding and need for in vivo studies.
Authors
Asmita Singh, University School of Basic & Applied Sciences, Guru Gobind Singh Indraprastha University, Dwarka, New Delhi, 110078, India
Mansi, University School of Basic & Applied Sciences, Guru Gobind Singh Indraprastha University, Dwarka, New Delhi, 110078, India
Pankaj Khanna, Department of Chemistry, Acharya Narendra Dev College, University of Delhi, Kalkaji, New Delhi, 110019, India
Deepshikha Gupta, Department of Chemistry, Amity Institute of Applied Sciences, Amity University, Sec. 125, Uttar Pradesh, Noida, 201301, India
Sandeep Kumar Singh, Associate Professor, Jindal Global Business School, O.P. Jindal Global University, Sonipat, Haryana, India
Leena Khanna, University School of Basic & Applied Sciences, Guru Gobind Singh Indraprastha University, Dwarka, New Delhi, 110078, India
Summary
Obesity has become a widespread health issue, often leading to serious conditions like fatty liver disease, type 2 diabetes, and heart disease. A significant factor in obesity is the build-up of triglycerides, with diacylglycerol acyltransferase (DGAT1) being a key enzyme involved in triglyceride synthesis and a potential target for treatment. This study explored the potential of morpholino pyrimidine/pyrimidino-oxazine as DGAT1 inhibitors using computational methods. A library of 250 compounds from PubChem and ZINC databases was docked against DGAT1 (PDB ID: 6VP0), yielding binding energies between −6.0 and −11.6 kcal/mol. ADME and physicochemical assessments narrowed these to the top 20 candidates. A 2D-QSAR model (R2 = 0.928, Q2 = 0.624) was created using known DGAT1 inhibitors and predicted -LogIC50 values for the top compounds showed close alignment. Furthermore, molecular dynamics simulations (100 ns), three sets of short MD run for 25 ns and principal component analysis (PCA) were conducted on the top two hits, PubChem CID155551474 and CID46268159. The results demonstrated stable complexes with DGAT1, with CID155551474 exhibiting superior performance. MMPBSA analysis confirmed binding stability with maximum energy at −300.42 ± 12.41 kJ/mol. This work is the first to suggest morpholino-pyrimidine and pyrimidino-oxazine derivatives as DGAT1 inhibitors, recommending further in vivo studies to confirm therapeutic efficacy.
Published in: ChemistrySelect
To read the full article, please click here.
