In Silico discovery of Histone-lysine N-methyltransferase SETD2 inhibitors.Torres, Juan C. and Montañez, GretelUPR Cayey, ...
Histone   methyltransferases          (HMTs)     order the DNA into structural units calledtransfer a methyl group from th...
the methylation of histone proteins and          models shown in figure 1. As a result, athus preventing cancer outgrowth....
development. Two distinct pharmacophoreCompound             Affinity                                      Model           ...
results, the next steps is to obtain/purchase    histone methylation (Tamaru and Selkersome of the predicted high affinity...
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In silico discovery of histone methyltranferase 1


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In silico discovery of histone methyltranferase 1

  1. 1. In Silico discovery of Histone-lysine N-methyltransferase SETD2 inhibitors.Torres, Juan C. and Montañez, GretelUPR Cayey, Puerto RicoAbstractProtein methyltranferase have been linked to a series of genetic diseases andaberrations.Histone methyltransferases (HMTs) methyl group is transferred from a donormolecule, which is usually Sulfur-adenosyl methionine; SAM, to an acceptor. The proteinmethyltransferases (PMTs) have emerged as a novel target class in the area of oncologybecause they have been identified with the influence of cancer tumor genesis. Using severalsoftware and databases, two Pharmacophore models were created and screened to obtainpossible lead-like compounds. As a result, only five pieces of the database were used for thescreening of the models and was able to filter 20% of the database that was screened. A total31,669 compounds where docked In Silico to the target protein and the results rankedaccording to their predicted binding energies and 58 drugs had binding energies from -9.7 to-9.0. This In Silico process focused in finding potential lead compounds that will inhibit themethylation of histone proteins and thus preventing cancer outgrowth.Introduction transferedfrom a donor molecule, which isThis investigation project is part of a usually Sulfur-adenosyl methionine; SAM,bigger scale investigation in which a RISE to an acceptor. The methylation occurs onstudent is working with methyltranferases, nucleic bases in DNA or amino acids inin the Dengue virus. Recently, it has been protein structures. There have been severaldiscovered thatmethyltranferases are also methyltransferasesidentified, includinginvolved in cancer. Methyltransferase, also DNA methyltransferase,known as methylase, is a tranferase tRNAmethyltransferase and proteinenzyme type in which a methyl group is methyltransferase.
  2. 2. Histone methyltransferases (HMTs) order the DNA into structural units calledtransfer a methyl group from the cofactor nucleosomes.S-adenosyl methionine to lysine or Methylation of histones is importantarginine residues on histone tails, thereby biologically, as it is the principalregulating chromatin compaction, binding epigenetic modification of chromatin thatof effector proteins and gene transcription. determines gene expression, genomicHMTs constitute an emerging target class stability, etc. Furthermore some abnormalin diverse disease areas, and selective expression or activity of methylation-chemical probes are necessary for target regulating enzymes has been noted in somevalidation (Campagna et al. 2011). types of human cancers, suggestingConsistent with the histone code, recent associations between histone methylationstudies indicate that methylation of histone and malignant transformation of cells orH3 lysine 9 (H3 Lys9), a modification formation of tumors (Duns et al. 2010). Itassociated with transcriptionally silent is now generally accepted that in additionheterochromatin, is critical for long-range to genetic aberrations, cancer can bechromatin regulatory processes (Rice et al. initiated by epigenetic changes in which2003). gene expression is altered without genomic This investigation work is with protein abnormalities.methyltranferases focusing in histone The protein methyltransferases (PMTs)methyltranferases, which are histone- have emerged as a novel target class,modifying enzymes. These groups of especially for oncology indications whereenzymes catalyze the transfer of three specific genetic alterations, affecting PMTmethyl groups to lysine. Histones are activity, drive cancer tumor genesis. Thishighly alkaline proteins found in In Silico process focused in findingeukaryotic cell nuclei that package and potential lead compounds that will inhibit
  3. 3. the methylation of histone proteins and models shown in figure 1. As a result, athus preventing cancer outgrowth. total of 18,082 compounds fulfilled all theMethodology requirements of Model 1, while 13,587The 3D structure of the protein Histone- compounds where obtained with Model 2.lysine N-methyltransferase SETD2 was Out of both models 21% of thesedownloaded from Investigators compounds where selected. In Figure 2,identified a new target for drug the table demonstrates the lead-likedevelopment in the Histone-lysine N- compounds in ranking binding energy. Themethyltransferase SETD2 by analysis of highest binding energy was -9.7 and from -benzene mapping and the interactions of 9.7 to -9.0 there were 58 drugs.previously identified compounds. Usingthe information of the previously identifiedcompounds, we created twoPharmacophore Models, using the softwareLigandScout, for the selected target andperformed a virtual pre-screening of Drug Pharmacophore Model 01Databases against our models. Finally, asecondary screening to identify “top-hits”or potential lead compounds by rankingbinding energy also using the softwareAutoDockVina was performed. Pharmacophore Model 02Results Figure 1. The two Pharmacophore Models that where created and used to screen the databasesA database, of approximately 150,000 for potential lead-like compounds.lead-like compounds, was used for thescreening against our two Pharmacophore
  4. 4. development. Two distinct pharmacophoreCompound Affinity Model models where generated and used to filterName (kcal/mol) the original database of small chemical1 MTHLY_01 -9.7 M01_0.32 MTHLY_02 -9.5 M02_0.0 compounds to less than 20% of the total3 MTHLY_03 -9.4 M01_0.24 MTHLY_04 -9.4 M02_0.3 number of compounds.5 MTHLY_05 -9.4 M01_0.3 A total of 31,669 compounds where6 MTHLY_06 -9.3 M01_0.47 MTHLY_07 -9.3 M01_0.3 docked In Silico to the target protein and8 MTHLY_08 -9.3 M02_0.29 MTHLY_09 -9.3 M02_0.0 the results ranked according to their10 MTHLY_10 -9.3 M02_0.411 MTHLY_11 -9.3 M01_0.3 predicted binding energies. A group of12 MTHLY_12 -9.3 M02_0.4 drug-like-compounds with high binding13 MTHLY_13 -9.3 M02_0.214 MTHLY_14 -9.3 M02_0.3 energies (less than -9.0 kcal/mol) was15 MTHLY_15 -9.3 M02_0.416 MTHLY_16 -9.3 M01_0.3 identified in the secondary screening17 MTHLY_17 -9.3 M02_0.018 MTHLY_18 -9.3 M02_0.3 consistent with the possibility of high19 MTHLY_19 -9.2 M02_0.4 affinity interactions. Our screenings with20 MTHLY_20 -9.2 M01_0.521 MTHLY_21 -9.2 M01_0.2 our models gave great results for just being22 MTHLY_22 -9.2 M02_0.223 MTHLY_23 -9.2 M02_0.2 a pilot investigation.24 MTHLY_24 -9.2 M02_0.225 MTHLY_25 -9.2 M02_0.0 For future work we would complete theFigure 2. The list of the top 25 drugs with ranking screening of the lead-like database, whichbinding energy. This gives the possibility that someof these lead-like compounds could be potential is about 1.7 million compounds, using bothdrugs that would inhibit the methylation process. Pharmacophore models. The results of theConclusion top-hits are evaluated and if appropriateInitial analysis of the Histone-lysine N- ranking binding energy, the informationmethyltransferase SETD2 suggests that the would be used to refine the Pharmacophorebinding site for the methyl donor model and repeat the screening cycle. Ifcompound SAM can be used as potential the refinement of the model gives goodtargets for In Silico drug discovery and
  5. 5. results, the next steps is to obtain/purchase histone methylation (Tamaru and Selkersome of the predicted high affinity 2001). Leading to a potential area ofcompounds and testtheir potential as possible future work in the correlationinhibitors in a bioassay. Also, it has been between DNA and protein methylation.noted that DNA methylation depends onAcknowledgmentJuan Carlos Torres and Gretel Montañez acknowledge the RISE program for funding. Thiswork was mentored by Dr. Hector Maldonado and his student co-worker Adriana Díaz.ReferenceCampagna V, Wai M, Nguyen K, Feher M, Najmanovich R, and Schapira M. 2011.Structural Chemistry of the Histone Methyltransferases Cofactor Binding Site. Chem. Inf. Model. 51:612–623Duns G, Berg E, Duivenbode I, Osinga J, Hollema H, Hofstra R, and Kok K. 2010. Histone Methyltransferase Gene SETD2 Is a Novel Tumor Suppressor Gene in Clear Cell Renal Cell Carcinoma. Cancer Res. 70:4287-4291Rice J, Briggs S, Ueberheide B, Barber C, Shabanowitz J, Hunt D, Shinkai Y and Allis D. 2003. Histone Methyltransferases Direct Different Degrees of Methylation to Define Distinct Chromatin Domains. 12: 1591–1598Spannhoff A, Hauser A, Heinke R, Sippl W, and Jung M. 2009.The Emerging Therapeutic Potential of Histone Methyltransferase and Demethylase Inhibitors.ChemMedChem. 4:1568-1582Tamaru H and Selker E. 2001. A histone H3 methyltransferase controls DNA methylation in Neurosporacrassa. Nature. 414:277-283.