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Robust Modeling and Scaffold Hopping: Case Study Based on HIV Reverse Transcriptase Inhibitors Type-1 Data

[ Vol. 12 , Issue. 6 ]

Author(s):

Girinath G. Pillai, Laznier Mederos, Chandramukhi S. Panda, Amber Gronski, Peeter Burk, Charles D. Hall, Alan R. Katritzky, Kaido Tämm and Mati Karelson   Pages 513 - 526 ( 14 )

Abstract:


Background: Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS occurs across mucosal surfaces or by direct inoculation.

Objective: The objective of this study was to consider chemically diverse scaffold sets of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) subjected to ideal oriented QSAR with large descriptor space.

Method: We generated a four-parameter QSAR model based on 111 data points, which provided an optimum prediction of HIV-1 RTI for overall 367 experimentally measured compounds.

Results: The robustness of the model is demonstrated by its statistical validation (Ntraining = 111, R2 = 0.85, Q2lmo = 0.84) and by the prediction of HIV-1 inhibition activity for experimentally measured compounds.

Conclusion: Finally, 5 novel hit compounds were designed in silico by using a virtual screening approach. The new hits met all the pharmacophore constraints and predicted pIC50 values within the binding ability of HIV-1 RT protein targets.

Keywords:

Global QSAR, applicability domain, diverse scaffolds, field points, scaffold hopping.

Affiliation:

Department of Chemistry, University of Tartu, Ravila 14a, Tartu 50411, Estonia.

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