Novel insight into the structural requirements of P70S6K inhibition using group-based quantitative structure activity relationship (GQSAR) (GQSAR)

Abdullahi, Abubakar Danjuma and Mohammed Abdul Kader, Abdul Rahman and Abdul Samat, Nadia Hanis and Mohamed, Farahidah and Muhammad, Bala Yauri and Mohammed, Helaluddin Abul bashar and Aljarbou, Ahmed and Kasmuri, Abdul Razak (2014) Novel insight into the structural requirements of P70S6K inhibition using group-based quantitative structure activity relationship (GQSAR) (GQSAR). Journal of Applied Pharmaceutical Science, 4 (6). pp. 16-24. ISSN 2231-3354

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Abstract

Dysregulation of P70 ribosomal S6 kinase (P70S6K) has been observed in many cancers; therefore, the design of new molecules targeting p70S6K of paramount importance in cancer therapy. The current study employed a group-based quantitative structure-activity relationship (GQSAR) to develop global QSAR models capable of predicting the bioactivity of P70S6K inhibitors. A wide variety of chemical structures and biological activities (half maximal inhibitory concentration) of P70S6K inhibitors were collected from the binding database website. Compounds were classified into various chemical groups and then fragmented into R1, R2, and R3 fragments based on certain pharmacophoric features required for ligand-target biointeractions. Different two-dimensional fragment-based descriptors were calculated for each fragment. The dataset was then divided into a training set (n=40) and a test set (n=10) using a sphere exclusion algorithm. Multiple linear regressions coupled with simulated annealing or stepwise regression resulted in model A (r2=0.92) and model B (r2=0.87), respectively. Leave-one-out validation showed that models A and B have internal predictive abilities of 72% and 61%, respectively. External validation indicated that both models are robust, with squared cross-correlation coefficients of the training set (pred-r2) of 0.87 and 0.89, respectively. The developed GQSAR models indicate that fragment R3 plays a key role in activity variation (65%) with sound contribution of five-membered rings (5 chain count), aromatic carbons (SaaaCE-index), and aromatic nitrogens (SaaNcount). In contrast, fragments R1 and R2 together contribute 35% of activity variation, suggesting that sulfur atoms (Sulfur count) and hydrophobic threemembered rings (chi3 chain) at R1 are preferable for inhibitory activity.

Item Type:	Article (Journal)
Additional Information:	5263/41555
Uncontrolled Keywords:	Descriptors; electrotopological indices; P70 ribosomal S6 kinase; quantitative structure activity relationship; regression analysis; simulated annealing, sphere exclusion
Subjects:	R Medicine > RS Pharmacy and materia medica
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Pharmacy > Department of Pharmaceutical Technology
Depositing User:	Assoc Prof Farahidah Mohamed
Date Deposited:	03 Mar 2015 12:09
Last Modified:	21 Sep 2017 20:23
URI:	http://irep.iium.edu.my/id/eprint/41555

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