QUANTUM MODELLING OF SOME POTENT, NON-TOXIC ANTIMALARIAL COMPOUNDS
QUANTUM MODELLING OF SOME POTENT, NON-TOXIC ANTIMALARIAL COMPOUNDS
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Date
2016-12
Authors
IBRAHIM, ZAKARI YA‘U
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Abstract
The Quantitative structure-activity relationship (QSAR) analyses were carried out for series of 45 naphthylisoquinoline and 22 bisbenzylisoquinoline alkaloids to find out the structural requirements of their antimalarial activities as well as the cytotoxicity using molecular descriptors. All the structures before the calculation of the descriptors were fully optimised in Spartan 14 v.1.1.0 using density functional B3LYP and the standard Pople‘s basis set of 6-311G*. The combination of the Genetic algorithm (GA) and Multiple Linear Regression (MLR) analyses methods were applied to derive QSAR models from the descriptors. For the selection of the best descriptors, the elimination selection stepwise regression method was utilised. The statistically significant models with parameters; R2 = 0.7483, Q2 = 0.6042 for activity of naphthylisoquinoline and R2 = 0.6256, Q2 = 0.7865 for the cytotoxicity were obtained. Furthermore, the models for activity and cytotoxicity of bisbenzylisoquinoline give R2 = 0.8845, Q2 = 0.7942 and R2 = 0.8742, Q2 = 0.7115 statistical parameters, respectively. The activity models generated, revealed descriptors BCUTc-1l (encoding connectivity information and atomic properties of the molecule), SssCH2 (the electro-topological state indices for number of –CH2 group connected with two double single bonds), minHsOH (electrotopological state atom type descriptor), Wlambda2.unity (encoding molecular 3D information regarding molecular size, shape, symmetry), μ, dipole moment and logP, lipophilicity, to be responsible for the activities of naphthylisoquinoline, while from the cytotoxicity models, MDEC-33 descriptor, which stand for molecular distance edge between all tertiary and quaternary carbons, determined the cytotoxicity. In the bisbenzylisoquinoline alkaloids, the descriptors responsible for the activities are BCUTw-1h (encode atomic properties relevant to intermolecular interactions), CrippenlogP, lipophilicity and maxssO (electrotopological state atom type descriptor) while ATSc4 (autocorrelation descriptor, weighted by charges), VCH-6 (describing the overall topology of the molecules) and SHBint9 (strength for potential hydrogen bonds of path length 9) descriptors causes cytotoxicity. The accuracy of the proposed MLR models were illustrated using the following evaluation techniques: cross validation, validation through an external test sets, and Y-randomisation. Furthermore, the domain of applicability which indicates the area of reliable predictions was defined. The good correlation between experimental and predicted biological activity/cytotoxicity for the four selected models further highlights the reliability of the constructed QSAR models.
Description
A DISSERTATION SUBMITTED TO THE SCHOOL OF POSTGRADUATE STUDIES,
AHMADU BELLO UNIVERSITY, ZARIA
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE AWARD OF A MASTER OF SCIENCE DEGREE IN PHYSICAL CHEMISTRY
DEPARTMENT OF CHEMISTRY,
FACULTY OF PHYSICAL SCIENCE,
AHMADU BELLO UNIVERSITY,
ZARIA, NIGERIA.
Keywords
QUANTUM MODELLING,, NON-TOXIC ANTIMALARIAL COMPOUNDS