title: Design of novel leads: ligand based computational modeling studies on non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1.
abstract: Researchers are on the constant lookout for new antiviral agents for the treatment of AIDS. In the present work, ligand based modeling studies are performed on analogues of substituted phenyl-thio-thymines, which act as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and novel leads are extracted. Using alignment-dependent descriptors, based on group center overlap (SALL, HDALL, HAALL and RALL), an alignment-independent descriptor (S log P), a topological descriptor (Balaban index (J)) and a 3D descriptor dipole moment (μ) and shape based descriptors (Kappa 2 index ((2)κ)), a correlation is derived with inhibitory activity. Linear and non-linear techniques have been used to achieve the goal. Support Vector Machine (SVM, R = 0.929, R(2) = 0.863) and Back Propagation Neural Network (BPNN, R = 0.928, R(2) = 0.861) methods yielded near similar results and outperformed Multiple Linear Regression (MLR, R = 0.915, R(2) = 0.837). The predictive ability of the models are cross-validated using a test dataset (SVM: R = 0.846, R(2) = 0.716, BPNN: R = 0.841, R(2) = 0.707 and MLR: R = 0.833, R(2) = 0.694). It is concluded that the hydrophobicity (S log P) and the polarity (μ) of a ligand and the presence of hydrogen donor (HDALL) moieties are the deciding factors in improving antiviral activity and pharmaco-therapeutic properties. Based on the above findings, a virtual dataset is created to extract probable leads with reasonable antiviral activity as well as better pharmacophoric properties.
authors.affiliation: Department of Applied Chemistry, Shri G.S. Institute of Technology and Sciences, Indore, MP 452001, India. nsapre@sgsits.ac.in sukusap@yahoo.com.
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Jain Pancholi
authors.forename: Swagata
authors.initials: S
authors.lastname: Gupta
authors.forename: Neelima
authors.initials: N
authors.lastname: Sapre
authors.forename: Nitin S
authors.initials: NS
authors.lastname: Sapre
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects*; D008024:Ligands; D016014:Linear Models; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D060388:Support Vector Machine; D013941:Thymine / Q000031:analogs & derivatives*
chemical_list: D019380:Anti-HIV Agents; D008024:Ligands; D018894:Reverse Transcriptase Inhibitors; D013941:Thymine