title: Energy-Based Pharmacophore and Three-Dimensional Quantitative Structure--Activity Relationship (3D-QSAR) Modeling Combined with Virtual Screening To Identify Novel Small-Molecule Inhibitors of Silent Mating-Type Information Regulation 2 Homologue 1 (SIRT1).
abstract: Silent mating-type information regulation 2 homologue 1 (SIRT1), being the homologous enzyme of silent information regulator-2 gene in yeast, has multifaceted functions. It deacetylates a wide range of histone and nonhistone proteins; hence, it has good therapeutic importance. SIRT1 was believed to be overexpressed in many cancers (prostate, colon) and inflammatory disorders (rheumatoid arthritis). Hence, designing inhibitors against SIRT1 could be considered valuable. Both structure-based and ligand-based drug design strategies were employed to design novel inhibitors utilizing high-throughput virtual screening of chemical databases. An energy-based pharmacophore was generated using the crystal structure of SIRT1 bound with a small molecule inhibitor and compared with a ligand-based pharmacophore model that showed four similar features. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed and validated to be employed in the virtual screening protocol. Among the designed compounds, Lead 17 emerged as a promising SIRT1 inhibitor with IC50 of 4.34 μM and, at nanomolar concentration (360 nM), attenuated the proliferation of prostate cancer cells (LnCAP). In addition, Lead 17 significantly reduced production of reactive oxygen species, thereby reducing pro inflammatory cytokines such as IL6 and TNF-α. Furthermore, the anti-inflammatory potential of the compound was ascertained using an animal paw inflammation model induced by carrageenan. Thus, the identified SIRT1 inhibitors could be considered as potent leads to treat both cancer and inflammation.
authors.affiliation: Computer-Aided Drug Design Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani , Hyderabad Campus, Hyderabad-500078, Telangana, India.
authors.forename: Venkat Koushik
authors.initials: VK
authors.lastname: Pulla
authors.affiliation: Computer-Aided Drug Design Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani , Hyderabad Campus, Hyderabad-500078, Telangana, India.|Incozen Therapeutics Private Limited, 450, Alexandria Knowledge Park, Phase-I, Shameerpet, Hyderabad-500078, Telangana, India.
authors.forename: Dinavahi Saketh
authors.initials: DS
authors.lastname: Sriram
authors.affiliation: Incozen Therapeutics Private Limited, 450, Alexandria Knowledge Park, Phase-I, Shameerpet, Hyderabad-500078, Telangana, India.
authors.forename: Srikant
authors.initials: S
authors.lastname: Viswanadha
authors.affiliation: Computer-Aided Drug Design Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani , Hyderabad Campus, Hyderabad-500078, Telangana, India.|Yogee's Bioinnovations Private Limited, Room 5, Technology Business Incubator, BITS-Pilani, Hyderabad campus, Shameerpet, Hyderabad-500078, Telangana, India.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.affiliation: Computer-Aided Drug Design Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani , Hyderabad Campus, Hyderabad-500078, Telangana, India.|Yogee's Bioinnovations Private Limited, Room 5, Technology Business Incubator, BITS-Pilani, Hyderabad campus, Shameerpet, Hyderabad-500078, Telangana, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014584:User-Computer Interface
chemical_list: D056572:Histone Deacetylase Inhibitors; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D054852:Small Molecule Libraries; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3; C447939:SIRT1 protein, human; D056564:Sirtuin 1