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Structural findings of quinolone carboxylic acids in cytotoxic, antiviral, and anti-HIV-1 integrase activity through validated comparative molecular modeling studies

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Abstract

Validated comparative 2D- and 3D-QSAR modeling and docking studies were performed for forty-five quinolone carboxylic acids having cytotoxic, antiviral, and anti-HIV-1 IN activity. Statistically significant 2D-QSAR model was developed through MLR and PLS analyses on unsplitted as well as splitted dataset and validated. The models were validated on external set compounds. Chemical potential, Mulliken charge at C8, and ETSA index at C3 are important for cytotoxicity. Global hardness, electrophilic frontier electron density at C10, ETSA index at O21, and C13 play pivotal role for antiviral activity. Mulliken charge at C5, ETSA index at C14, RTSA index at C8, and C13 and LUMO density on C7 are important for anti-HIV-1 IN activity. HQSAR study suggested that maximum contributing fragments include C2 and C14 and substitutions at C13 and C14 for anti-HIV-1 IN activity and antiviral activity, respectively. The positively contributing fragments include C8, C9, C10, C11, and C16 are beneficial for cytotoxicity. CoMFA study suggested that favorable steric region located near C14 is important for anti-HIV-1 IN activity, steric factor at C8 substitution is important for antiviral and cytotoxicity activities. CoMSIA study correlates the steric region found in CoMFA study; hydrophobic favorable regions are located around C8 and near C13. For antiviral activity, unfavorable hydrogen bond acceptor region is observed near C8 substitution, favorable hydrogen bond acceptor region is observed at N1 substitution. For cytotoxic activity, favorable electrostatic region is located around quinolone and benzene ring. Docking study suggested that Glu152, Gln148, and Asn155 residues of the HIV-1 integrase enzyme bind with the molecule.

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Notes

  1. Mouse is a computer program written in C++ program developed in our laboratory.

Abbreviations

k-MCA:

k-Means cluster analysis

PRESS:

Predicted residual sum of squares

QSAR:

Quantitative structure–activity relationship

SDEP:

Standard deviation of error of prediction

HQSAR:

Hologram quantitative structure–activity relationship

CoMFA:

Comparative Molecular Field Analysis

CoMSIA:

Comparative Molecular Similarity Analysis

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Acknowledgments

Authors are thankful to the All India Council for Technical Education (AICTE), New Delhi, Council of Scientific and Industrial Research (CSIR), New Delhi and University Grants Commission (UGC), New Delhi for providing financial support. Two authors (NA and AKH) thank Council of Scientific and Industrial Research (CSIR), New Delhi for providing Senior Research Fellowship (SRF). We are also thankful to the authority of Jadavpur University for providing us the facility required for the work.

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  1. Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, 700032, India

    Nilanjan Adhikari, Amit Kumar Halder, Chanchal Mondal & Tarun Jha

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  1. Nilanjan Adhikari
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  2. Amit Kumar Halder
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Correspondence to Tarun Jha.

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Adhikari, N., Halder, A.K., Mondal, C. et al. Structural findings of quinolone carboxylic acids in cytotoxic, antiviral, and anti-HIV-1 integrase activity through validated comparative molecular modeling studies. Med Chem Res 23, 3096–3127 (2014). https://doi.org/10.1007/s00044-013-0897-5

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