title: Structure-based drug design of small molecule SIRT1 modulators to treat cancer and metabolic disorders.
abstract: Sirtuins comprise a family of deacetylase enzymes that catalyze the removal of an acetyl moiety from the ɛ-amino group of lysine residues within protein targets. Sirtuin 1(SIRT1), a NAD(+) dependent class III histone deacetylase is involved in a variety of human disorders such as obesity, type II diabetes, cancer and aging. Inhibition of SIRT1 could be useful for cancer treatment while activators can be useful for longevity and treating metabolic disorders. Hence we undertook an effort to design both inhibitors and activators using structure-based drug design techniques and report here the biological proof of concept. In this paper, we report diverse small molecule inhibitors with a potential to attenuate cancer growth designed based on high-throughput virtual screening and docking using the crystal structure of SIRT1. And small molecule activators with potential to suppress adipogenesis differentiation indicating their usefulness in obesity control was designed based on a homology model of SIRT1 activator domain.
authors.affiliation: Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, A.P., India.
authors.forename: Venkat Koushik
authors.initials: VK
authors.lastname: Pulla
authors.affiliation: Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, A.P., India.
authors.forename: Mallika
authors.initials: M
authors.lastname: Alvala
authors.affiliation: Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, A.P., India; Incozen Therapeutics Private Limited, Spectrum Discovery Zone, Alexandria Knowledge Park, Phase-I, Shameerpet, Hyderabad 500078, A.P., India.
authors.forename: Dinavahi Saketh
authors.initials: DS
authors.lastname: Sriram
authors.affiliation: Incozen Therapeutics Private Limited, Spectrum Discovery Zone, Alexandria Knowledge Park, Phase-I, Shameerpet, Hyderabad 500078, A.P., India.
authors.forename: Srikant
authors.initials: S
authors.lastname: Viswanadha
authors.affiliation: Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, A.P., India.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.affiliation: Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, A.P., India. Electronic address: pyogee@hyderabad.bits-pilani.ac.in.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D015195:Drug Design; D057075:Enzyme Assays; D005453:Fluorescence; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008659:Metabolic Diseases / Q000188:drug therapy*; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*; D056564:Sirtuin 1; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D056564:Sirtuin 1
keywords: Adipogenesis differentiation; Cell-cycle analysis; Docking; High-through virtual screening; SIRT1 activators; SIRT1 inhibitors