title: Exploring isoxazole and carboxamide derivatives as potential non-nucleoside reverse transcriptase inhibitors.
abstract: Nonnucleoside reverse transciptase inhibitors (NNRTI) are a class of drug molecules with a specific target of HIV-1 reverse transcriptase (RT). In the present work, we evaluated a set of selected oxazole and carboxamide derivatives to identify potential pharmacophoric features using molecular docking approach. The docking approach employed has been validated by enrichment factor calculation at top 1% (EF1%). It shows a considerable improvement in EF1%value compared to earlier reported study carried out on specific dataset of ligands and decoys for RT, in the directory of useful decoys (DUD). The carboxamide derivatives show better activity as NNRT inhibitors than oxazole derivatives. From this study, four pharmacophoric groups including a triazine ring, an aniline substituent, a benzyl amide moiety and a trimethylphenoxy substituent have been recognized and used for designing new NNRT inhibitors. Newly designed molecules show significant enhancement in docking scores over the native ligand, parent and other training set molecules. In addition, some functional groups have also been identified to assist in improving the activity of these pharmacophores. Thus a nitrile group, an amide and fluoro substitution turn out to be an important requisite for NNRT potential inhibitors.
authors.affiliation: Department of Chemistry, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400019, India.
authors.forename: Sudheer S
authors.initials: SS
authors.lastname: Kurup
authors.affiliation: Department of Chemistry, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai 400019, India. Electronic address: ka.joshi@ictmumbai.edu.in.
authors.forename: Kaustubh A
authors.initials: KA
authors.lastname: Joshi
mesh_terms: D000577:Amides / Q000737:chemistry*; D000814:Aniline Compounds / Q000737:chemistry; D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000737:chemistry* / Q000201:enzymology; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007555:Isoxazoles / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014227:Triazines / Q000737:chemistry
chemical_list: D000577:Amides; D000814:Aniline Compounds; D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D008024:Ligands; D014227:Triazines; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Enrichment factor; Hydrogen bonded interaction; Molecular docking; NNRTI