title: Pyridones as NNRTIs against HIV-1 mutants: 3D-QSAR and protein informatics.
abstract: CoMFA and CoMSIA based 3D-QSAR of HIV-1 RT wild and mutant (K103, Y181C, and Y188L) inhibitory activities of 4-benzyl/benzoyl pyridin-2-ones followed by protein informatics of corresponding non-nucleoside inhibitors' binding pockets from pdbs 2BAN, 3MED, 1JKH, and 2YNF were analysed to discover consensus features of the compounds for broad-spectrum activity. The CoMFA/CoMSIA models indicated that compounds with groups which lend steric-cum-electropositive fields in the vicinity of C5, hydrophobic field in the vicinity of C3 of pyridone region and steric field in aryl region produce broad-spectrum anti-HIV-1 RT activity. Also, a linker rendering electronegative field between pyridone and aryl moieties is common requirement for the activities. The protein informatics showed considerable alteration in residues 181 and 188 characteristics on mutation. Also, mutants' isoelectric points shifted in acidic direction. The study offered fresh avenues for broad-spectrum anti-HIV-1 agents through designing new molecules seeded with groups satisfying common molecular fields and concerns of mutating residues.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Utsab
authors.initials: U
authors.lastname: Debnath
authors.forename: Saroj
authors.initials: S
authors.lastname: Verma
authors.forename: Surabhi
authors.initials: S
authors.lastname: Jain
authors.forename: Setu B
authors.initials: SB
authors.lastname: Katti
authors.forename: Yenamandra S
authors.initials: YS
authors.lastname: Prabhakar
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D019380:Anti-HIV Agents / Q000737:chemistry; D001665:Binding Sites; D030562:Databases, Protein; D015195:Drug Design; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry
chemical_list: D000596:Amino Acids; D019380:Anti-HIV Agents; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors