Path Pendeccentric Connectivity Indices: Detour Matrix Based Molecular Descriptors for QSAR/QSPR Studies, Part 2: Development of Models for TTK Inhibitory Activity of Acetamide/Carboxamide Analogs

Path Pendeccentric Connectivity Indices: Detour Matrix Based Molecular Descriptors for QSAR/QSPR Studies, Part 2: Development of Models for TTK Inhibitory Activity of Acetamide/Carboxamide Analogs

Naveen Khatri (Faculty of Pharmaceutical Sciences, Pt. B. D. Sharma University of Health Sciences, Rohtak, India) and A. K. Madan (Faculty of Pharmaceutical Sciences, Pt. B. D. Sharma University of Health Sciences, Rohtak, India)
DOI: 10.4018/IJQSPR.2017070107
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Abstract

A pivotal role of tyrosine threonine kinase (TTK) has been established in tumor initiation, survival of genomically unstable and aneuploid cancer cells. In present study, path pendeccentric connectivity indices reported in part 1 of the manuscript were successfully applied for developing models for predicting TTK inhibitory activity of acetamide/carboxamide analogs. Diverse 2D and 3D molecular descriptors (MDs) were successfully utilized for developing models using artificial neural networks (ANN) and moving average analysis (MAA). The overall accuracy of prediction achieved for ANN and MAA based models was up to 96% for the training set and up to 92% during cross validation. The statistical utility of the said models was also evaluated through Matthews correlation coefficient, non error rate, sensitivity and intercorrelation analysis. Low IC50 values obtained for active ranges of the proposed MAA based models indicate the tremendous potential of said models for furnishing lead molecules for developing potent TTK inhibiting acetamide/carboxamide analogs.
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Introduction

Despite tremendous progress and steep increase in R & D expenditure in the field of oncology research, cancer still remains a major worldwide health concern (Mou, Kesari, Wen, & Huang, 2011). Today the success of novel cancer therapies depends on identification of potential targets responsible for tumour initiation and survival (King et al., 2006). Therefore, there seems to be a paradigm shift in the development process of novel therapeutic agents for this dreadful disease. Accordingly, more attention is now being accorded to treatments that focus on specific molecular targets generated in cancer cells instead of non-specific cytotoxic chemotherapies that affect all dividing cells in the body (Harrison, Holen, & Liu, 2009). Uncontrolled proliferation of cells or abnormality in early stages of the cell cycle is one of the major causes in prognosis of human tumor/cancer (Jordan, & Wilson, 2004). Mitosis is a critical stage in the cell cycle which assures the consistent inheritance of the genetic material by the cellular family at the same time prohibiting chromosomal instability (CIN) and aneuploidy (Hanahan, & Weinberg, 2011; Gordon, Resio, & Pellman, 2012). The ubiquitous involvement of mitotic kinases in essentially all the signal transmitting pathways provides a clear cut indication for pursuing research towards developing targeted kinase inhibitors as anti-cancer agents (Miduturu et al., 2011). Tyrosine threonine kinase (TTK), also called monopolar spindle1 (MPS1) is amongst the top 25 genes abnormally unregulated in tumors of different origins (Malumbres, & Barbacid, 2007; Carter, Eklund, Kohane, Harris, & Szallasi, 2006; Carcer De, Perez de Castro, & Malumbres, 2007) and invariable with its expression in cell cycle evolution (Doua et al., 2004). Over expression of TTK may promote tumor initiation and survival of genomically unstable and aneuploid cancer cells (Kilpinen, Ojala, & Kallioniemi, 2010). Basically, TTK is a serine/threonine and tyrosine kinase that regulates chromosome alignment during mitosis (Malumbres, 2011). This family of dual specificity kinase is widely but not ubiquitously distributed in eukaryotes and constitutes an important element of spindle assembly checkpoint (SAC) (Jemaa et al., 2013). SAC pathway monitors transit via the cell cycle at various phases, i.e., mitotic spindle attachment at kinetochores during prometaphase, restrict anaphase initiation until all of the chromosomes made stable bipolar connection to centrosomes and correctly aligned at the metaphase plate (Musacchio, & Salmon, 2007; Teixeira et al., 2014). Deregulation of MPS1 kinase activity results in abnormal chromosome number or CIN and consequently, in aneuploidy (Hanahan, & Weinberg, 2011) which is an incessant feature of cancer cells and generally regarded as possible cause of carcinogenesis (Thompson, & Compton, 2008).

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