title: Atom based 3D-QSAR studies on 2,4-dioxopyrimidine-1-carboxamide analogs: Validation of experimental inhibitory potencies towards acid ceramidase.
abstract: Ceramide (Cer), the central lipid molecule in sphingolipid biosynthesis and degradation, which plays a key role in sphingolipid signaling, induces cell differentiation and apoptosis. Cellular degradation of ceramide to sphingosine is catalyzed by a family of ceramidases (CDases). Pharmacological inhibition of ceramidases and more particularly, acid ceramidase (aCDase) is suggestive of a chemotherapeutic approach as it increases the cellular concentration of ceramide inducing apoptosis. In the present report, we have utilized atom-based 3D-QSAR method to analyze the structural aspects on a series of 2,4-dioxopyrimidine-1-carboxamide (carmofur) derivatives as potent inhibitors of aCDase. In this approach the experimental dataset was divided into training (83%) and test (17%) sets and the best model was chosen based on randomized trial distributions consisting of five compounds in a test set with a wide range of activity profile and superior values of statistical parameters such as Q(2) and R(2) values. The reported experimental results by Piomelli and co-workers on the inhibition of aCDase by the carmofur derivatives were correlated using robust 3D-QSAR as well as docking methods. With careful structure-activity correlation studies the carmofur analogs were classified into four sub-categories (Set 1-4) to understand the effect of each structural features separately. This approach led us to short-list most active carmofur derivatives such as compounds 26, 30 and 32 with the incorporation of more than one structural features in a single molecule. However, the inhibition potency might further be enhanced by designing compound 33 upon the incorporation of all features in a single compound. Compound 33 that was missing in the experimental study by Piomelli and co-workers (J. Med. Chem. 2013, 56, 3518), could be identified using 3D-QSAR studies. Moreover, the importance of structural features in lead inhibitors such as 26, 30 and 32 along with 33 was further justified by their efficient molecular interactions at the active site of homology modeled protein human N-acyl ethanolamine hydrolyzing acid amidase (hNAAA) as evidenced by molecular docking study. Furthermore, efficient molecular interaction of some representative inhibitors with hNAAA led to the understanding that hNAAA could be a possible alternative of aCDase for developing potent inhibitors.
authors.affiliation: Department of Chemistry, Presidency University, 86/1 College Street, Kolkata 700 073, India.
authors.forename: Debojit
authors.initials: D
authors.lastname: Bhattacherjee
authors.affiliation: Department of Chemistry, Presidency University, 86/1 College Street, Kolkata 700 073, India; Department of Chemistry, Indian Institute of Technology, Guwahati 781 039, India. Electronic address: kbhabak@iitg.ernet.in.
authors.forename: Krishna Pada
authors.initials: KP
authors.lastname: Bhabak
mesh_terms: D055573:Acid Ceramidase / Q000737:chemistry*; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
chemical_list: D055573:Acid Ceramidase; C017367:carmofur; D005472:Fluorouracil
keywords: 3D-QSAR; AutoDock; Carmofur; Ceramidase; Ceramide; Chemotherapy; Sphingolipids