Tags

Type your tag names separated by a space and hit enter

Comparative validated molecular modeling of p53-HDM2 inhibitors as antiproliferative agents.
Eur J Med Chem. 2015 Jan 27; 90:860-75.EJ

Abstract

Tumor suppressor protein p53 regulates the cell cycle and inhibits tumor growth. It is inactivated by mutation or binding with human double minute 2 (HDM2) protein. The HDM2 is a promising target for treatment of p53 protein related cancers. Molecular modeling techniques such as 2D-QSAR, pharmacophore mapping and 3D-QSAR analyses were performed on 155 structurally diverse HDM2 inhibitors to understand structural and physicochemical requirements for higher activity. The linear and spline 2D-QSAR models were developed through multiple linear regression and genetic functional algorithm methods. The 2D-QSAR models suggested that number of fluorine, chlorine, tertiary nitrogen atoms as well as donor feature, stereogenic centers and higher value of solvent accessible surface area are important features in defining activity. Monte Carlo method was applied to generate QSAR models that determined structural indicators (alerts) for increase or decrease of the biological activity. Ligand-based pharmacophore mapping showed importance of two hydrophobic, one hydrophobic aromatic, one ring aromatic and one donor features. The structure-based pharmacophore model demonstrated significance of two hydrophobic, one ring aromatic and two acceptor features. The pharmacophore (ligand) aligned structures were subjected to 3D-QSAR analyses. The structure-based pharmacophore was also used for pharmacophore restraint molecular docking to analyze ligand-receptor interactions and for adjudging predictability as well as validation of different modeling techniques. These comparative molecular modeling techniques may help to design novel HDM2 inhibitors.

Authors+Show Affiliations

Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P.O. Box 17020, Jadavpur University, Kolkata 700032, India.Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P.O. Box 17020, Jadavpur University, Kolkata 700032, India.Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P.O. Box 17020, Jadavpur University, Kolkata 700032, India.Department of Chemical Technology, University of Calcutta, 92, APC Ray Road, Kolkata 700009, India.Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, West Bengal, India.Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar 470003, Madhya Pradesh, India.Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P.O. Box 17020, Jadavpur University, Kolkata 700032, India. Electronic address: tjupharm@yahoo.com.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Validation Study

Language

eng

PubMed ID

25535952

Citation

Mondal, Chanchal, et al. "Comparative Validated Molecular Modeling of p53-HDM2 Inhibitors as Antiproliferative Agents." European Journal of Medicinal Chemistry, vol. 90, 2015, pp. 860-75.
Mondal C, Halder AK, Adhikari N, et al. Comparative validated molecular modeling of p53-HDM2 inhibitors as antiproliferative agents. Eur J Med Chem. 2015;90:860-75.
Mondal, C., Halder, A. K., Adhikari, N., Saha, A., Saha, K. D., Gayen, S., & Jha, T. (2015). Comparative validated molecular modeling of p53-HDM2 inhibitors as antiproliferative agents. European Journal of Medicinal Chemistry, 90, 860-75. https://doi.org/10.1016/j.ejmech.2014.12.011
Mondal C, et al. Comparative Validated Molecular Modeling of p53-HDM2 Inhibitors as Antiproliferative Agents. Eur J Med Chem. 2015 Jan 27;90:860-75. PubMed PMID: 25535952.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparative validated molecular modeling of p53-HDM2 inhibitors as antiproliferative agents. AU - Mondal,Chanchal, AU - Halder,Amit Kumar, AU - Adhikari,Nilanjan, AU - Saha,Achintya, AU - Saha,Krishna Das, AU - Gayen,Shovanlal, AU - Jha,Tarun, Y1 - 2014/12/08/ PY - 2014/08/16/received PY - 2014/12/02/revised PY - 2014/12/06/accepted PY - 2014/12/24/entrez PY - 2014/12/24/pubmed PY - 2015/10/10/medline KW - 2D-QSAR KW - 3D-QSAR KW - Monte Carlo method KW - Pharmacophore mapping KW - p53-HDM2 SP - 860 EP - 75 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 90 N2 - Tumor suppressor protein p53 regulates the cell cycle and inhibits tumor growth. It is inactivated by mutation or binding with human double minute 2 (HDM2) protein. The HDM2 is a promising target for treatment of p53 protein related cancers. Molecular modeling techniques such as 2D-QSAR, pharmacophore mapping and 3D-QSAR analyses were performed on 155 structurally diverse HDM2 inhibitors to understand structural and physicochemical requirements for higher activity. The linear and spline 2D-QSAR models were developed through multiple linear regression and genetic functional algorithm methods. The 2D-QSAR models suggested that number of fluorine, chlorine, tertiary nitrogen atoms as well as donor feature, stereogenic centers and higher value of solvent accessible surface area are important features in defining activity. Monte Carlo method was applied to generate QSAR models that determined structural indicators (alerts) for increase or decrease of the biological activity. Ligand-based pharmacophore mapping showed importance of two hydrophobic, one hydrophobic aromatic, one ring aromatic and one donor features. The structure-based pharmacophore model demonstrated significance of two hydrophobic, one ring aromatic and two acceptor features. The pharmacophore (ligand) aligned structures were subjected to 3D-QSAR analyses. The structure-based pharmacophore was also used for pharmacophore restraint molecular docking to analyze ligand-receptor interactions and for adjudging predictability as well as validation of different modeling techniques. These comparative molecular modeling techniques may help to design novel HDM2 inhibitors. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/25535952/Comparative_validated_molecular_modeling_of_p53_HDM2_inhibitors_as_antiproliferative_agents_ DB - PRIME DP - Unbound Medicine ER -