title: Structure-based identification of drug-like inhibitors of p300 histone acetyltransferase.
abstract: A growing body of evidence suggests that p300 histone acetyltransferase plays important roles in cancer cell differentiation and proliferation. Here, we employed structure-based hierarchical virtual screening method to identify novel lead compounds of p300 histone acetyltransferase. From a screening library containing approximate 100 000 diverse druglike compounds, 33 compounds were chosen for experimental testing and one compound, 4-acetyl-2-methyl-N-morpholino-3,4-dihydro-2H-benzo[b][1, 4]thiazine-7-sulfonamide (17), showed as micromolar inhibitor. Based on its predicted binding pose, we investigated its binding characteristics by designing two series of structural modifications. The obtained structure-activity relationship results are consistent with the predicted binding model. We expect that the identified novel p300 histone acetyltransferase inhibitors will serve as starting points for further development of more potent and specific histone acetyltransferase inhibitors.
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
authors.forename: Fan-Qi
authors.initials: FQ
authors.lastname: Zeng
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Peng
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Li-Bing
authors.initials: LB
authors.lastname: Mu
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Zhi-Yuan
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Niu
authors.initials: N
authors.lastname: Huang
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C000604295:4-acetyl-2-methyl-N-morpholino-3,4-dihydro-2H-benzo(b)(1,4)thiazine-7-sulfonamide; D004791:Enzyme Inhibitors; D009025:Morpholines; D013449:Sulfonamides; D050880:p300-CBP Transcription Factors