Ensemble‐Based Virtual Screening and Experimental Validation of Inhibitors Targeting a Novel Site of Human DNMT 1

• Published in: Chemical biology & drug design 2016-07, Vol.88 (1), p.5-16
• Main Authors: Joshi, Manali, Rajpathak, Shriram N., Narwade, Santosh C., Deobagkar, Deepti
• Format: Article
• Language: English
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12741

Human DNA methyltransferase1 (h DNMT 1) is responsible for preserving DNA methylation patterns that play important regulatory roles in differentiation and development. Misregulation of DNA methylation has thus been linked to many syndromes, life style diseases, and cancers. Developing specific inhibitors of h DNMT 1 is an important challenge in the area since the currently targeted cofactor and substrate binding site share structural features with various proteins. In this work, we generated a structural model of the active form of h DNMT 1 and identified that the 5‐methylcytosine (5‐m C ) binding site of the h DNMT 1 is structurally unique to the protein. This site has been previously demonstrated to be critical for methylation activity. We further performed multiple nanosecond time scale atomistic molecular dynamics simulations of the structural model followed by virtual screening of the A sinex database to identify inhibitors targeting the 5‐m C site. Two compounds were discovered that inhibited h DNMT 1 in vitro , one of which also showed inhibition in vivo corroborating the screening procedure. This study thus identifies and attempts to validate for the first time a unique site of h DNMT 1 that could be harnessed for rationally designing highly selective and potent hypomethylating agents.