NDLI: K-nearest neighbor molecular field analysis based 3D-QSAR and in silico ADME/T studies of cinnamoyl derivatives as HIV-1 integrase inhibitors

Content Provider	Springer Nature Link
Author	Srivastav, V. K. Tiwari, M.
Copyright Year	2014
Abstract	A three-dimensional quantitative structure activity relationship (3D-QSAR) study was carried out on a dataset of 62 cinnamoyl derivatives as human immunodeficiency virus-1 integrase (HIV-1 IN) inhibitors using k-nearest neighbor molecular field analysis (kNN-MFA). QSAR models were developed using stepwise-forward selection (SWF), genetic algorithm (GA), and simulated annealing (SA) variable selection approaches. Selected QSAR models were validated internally [using cross-validated squared correlation coefficient (q 2)] and externally [using predicted squared correlation coefficient (pred_r 2) and Y randomization] to determine their predictive ability. SA-kNN-MFA model (q 2 = 0.7669, pred_r 2 = 0.7566) was considered as the best model due to its better predictive ability (higher pred_r 2 value) as compared to SWF-kNN-MFA (q 2 = 0.8956, pred_r 2 = 0.5905) and GA-kNN-MFA (q 2 = 0.6431, pred_r 2 = 0.7525) models in external validation. Steric and electrostatic field descriptors were favorable for HIV-1 IN inhibition activity in the best model. HIV-1 IN inhibition activity of an external dataset containing 22 compounds was predicted to check the applicability domain of developed models. Drug-likeness and in silico absorption, distribution, metabolism, excretion, and toxicity (ADME/T) studies were also performed to determine the pharmacokinetic and toxicity profile of dataset compounds. Subsequently, HIV-1 IN inhibition activity of 53 proposed compounds was predicted using developed models and their ADME/T properties were also calculated. Results of the present study suggested that 3D-QSAR model developed by SA-kNN-MFA method may be helpful to understand the structural requirement for HIV-1 IN inhibition and may support the designing of potent antiretroviral agents.
Starting Page	684
Ending Page	700
Page Count	17
File Format	PDF
ISSN	10542523
Journal	Medicinal Chemistry Research
Volume Number	24
Issue Number	2
e-ISSN	15548120
Language	English
Publisher	Springer US
Publisher Date	2014-07-22
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Cinnamoyl derivatives HIV-1 IN inhibition 3D-QSAR kNN-MFA ADME/T Pharmacology/Toxicology Biochemistry Cell Biology
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology, Toxicology and Pharmaceutics

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