title: Structure Based Library Design (SBLD) for new 1,4-dihydropyrimidine scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors.
abstract: The various scaffolds containing 1,4-dihydropyrimidine ring were designed by considering the environment of the active site of COX-1/COX-2 and 5-LOX enzymes. The structure-based library design approach, including the focused library design (Virtual Combinatorial Library Design) and virtual screening was used to select the 1,4-dihydropyrimidine scaffold for simultaneous inhibition of both enzyme pathways (COX-1/COX-2 and 5-LOX). The virtual library on each 1,4-dihydropyrimidine scaffold was enumerated in two alternative ways. In first way, the chemical reagents at R groups were filtered by docking of scaffold with single position substitution, that is, only at R1, or R2, or R3, … Rn on COX-2 enzyme using Glide XP docking mode. The structures that do not dock well were removed and the library was enumerated with filtered chemical reagents. In second alternative way, the single position docking stage was bypassed, and the entire library was enumerated using all chemical reagents by docking on the COX-2 enzyme. The entire library of approximately 15,629 compounds obtained from both ways after screening for drug like properties, were further screened for their binding affinity against COX-1 and 5-LOX enzymes using Virtual Screening Workflow. Finally, 142 hits were obtained and divided into two groups based on their binding affinity for COX-1/COX-2 and for both enzyme pathways (COX-1/COX-2 and 5-LOX). The ten molecules were selected, synthesized and evaluated for their COX-1, COX-2 and 5-LOX inhibiting activity.
authors.affiliation: Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, Maharashtra, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Lokwani
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad, India.
authors.forename: Rajaram
authors.initials: R
authors.lastname: Azad
authors.affiliation: Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, Maharashtra, India.
authors.forename: Aniket
authors.initials: A
authors.lastname: Sarkate
authors.affiliation: School of Life Sciences, University of Hyderabad, Hyderabad, India.
authors.forename: Pallu
authors.initials: P
authors.lastname: Reddanna
authors.affiliation: Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, Maharashtra, India. Electronic address: dbsdeepak10@rediffmail.com.
authors.forename: Devanand
authors.initials: D
authors.lastname: Shinde
mesh_terms: D000818:Animals; D020650:Combinatorial Chemistry Techniques; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D012756:Sheep
chemical_list: C586280:1,4-dihydropyrimidine; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011743:Pyrimidines
keywords: 1,4-Dihydropyrimidine; 5-LOX; COX-1; COX-2; Docking study; Structure Based Library Design (SBLD); Virtual Combinatorial Library Design; Virtual screening