De novo drug designing coupled with brute force screening and structure guided lead optimization gives highly specific inhibitor of METTL3: a potential cure for Acute Myeloid Leukaemia.

Expression of METTL3, a SAM dependent methyltransferase, which deposits m6A on mRNA is linked to poor prognosis in Acute Myeloid Leukaemia and other type of cancers. Down regulation of this epitranscriptomic regulator has been found to inhibit cancer progression. Silencing the methyltransferase activity of METTL3 is a lucrative strategy to design anticancer drugs. In this study 3600 commercially available molecules were screened against METTL3 using brute force screening approach. However, none of these compounds take advantage of the unique Y-shaped binding cavity of the protein, raising the need for de novo drug designing strategies. As such, 125 branched, Y-shaped molecules were designed by "stitching" together the chemical fragments of the best inhibitors that interact strongly with the METTL3 binding pocket. This results in molecules that have the three-dimensional structure and functional groups which enable it to fit in the METTL3 cavity like fingers in a glove, having unprecedented selectivity and binding affinities. The designed compounds were further refined based on Lipinski's rule, docking score and synthetic accessibility. The molecules faring well in these criteria were simulated for 100 ns to check the stability of the protein inhibitor complex followed by binding free energy calculation.Communicated by Ramaswamy H. Sarma.

Brute Force Virtual Drug Screening with Molecular Dynamics Simulation and MM/PBSA to Find Potent Inhibitors of METTL16.

Epitranscriptomic modification is a dynamic modification of RNAs. Epitranscriptomic writer proteins are methyltransferases, such as METTL3 and METTL16. The up regulation of METTL3 have been found to be linked to different cancers and targeting METTL3 is an effective way to reduce tumour progression. Drug development against METTL3 is an active field of research. METTL16, SAM dependent methyltransferase, is another writer protein, that has been found to be upregulated in hepatocellular carcinoma and gastric cancer. In this pioneering study METTL16 has been targeted for virtual drug screening for the very first time using brute force strategy to identify a drug molecule that could be repurposed for the treatment of the disease caused. An unbiased library of the commercially available drug molecules has been used for screening using a multipoint validation process developed for this work, which includes molecular docking, ADMET analysis, protein-ligand interaction analysis, Molecular Dynamics Simulation, binding energy calculation via Molecular Mechanics Poisson-Boltzmann Surface Area method. Upon the in-silico screening of over 650 drugs the authors have found NIL and VXL passed the validation process. The data strongly indicates the potency of these two drugs in the treatment of disease where METTL16 needs to be inhibited.

Amentoflavone and methyl hesperidin, novel lead molecules targeting epitranscriptomic modulator in acute myeloid leukemia: in silico drug screening and molecular dynamics simulation approach.

INTRODUCTION: M6A modification in transcriptome is critical in regulating different cellular processes, including cancer. In human beings, METTL3 is the major m6A writer that works in association with METTL14, an accessory protein. Extensive study revealed that cancer progression for acute myeloid leukemia, gastric cancer, colorectal cancer, hepatocellular carcinoma, and lung cancer is directly contributed by irregular expression of METTL3. OBJECTIVE: Targeting METTL3 has opened a new window in the development of novel inhibitors/drugs. METHODS: In this study, commercially available natural compounds were randomly screened to avoid the bias of screening small molecules on the basis of structural similarity. From 810 compounds that were screened, 80 commercially available compounds were showing better score when compared with the existing substrate/substrate-analogue and the inhibitor bound crystal structures in terms of docking score and binding energy calculation. RESULTS AND CONCLUSION: Among this pool of compounds, the best seven small molecules have been selected and further validated by different computational tools like binding energy calculation, molecular dynamics simulation, ADME analysis, and toxicity prediction. The novel hits found in this study can function as lead compounds which can be developed into inhibitors as well as drugs, specific against METTL3.

m6A mRNA Destiny: Chained to the rhYTHm by the YTH-Containing Proteins.

The control of gene expression is a multi-layered process occurring at the level of DNA, RNA, and proteins. With the emergence of highly sensitive techniques, new aspects of RNA regulation have been uncovered leading to the emerging field of epitranscriptomics dealing with RNA modifications. Among those post-transcriptional modifications, N6-methyladenosine (m6A) is the most prevalent in messenger RNAs (mRNAs). This mark can either prevent or stimulate the formation of RNA-protein complexes, thereby influencing mRNA-related mechanisms and cellular processes. This review focuses on proteins containing a YTH domain (for YT521-B Homology), a small building block, that selectively detects the m6A nucleotide embedded within a consensus motif. Thereby, it contributes to the recruitment of various effectors involved in the control of mRNA fates through adjacent regions present in the different YTH-containing proteins.