Adebayo A. Adeniyi

Comparing the Suitability of Autodock, Gold and Glide for the Docking and Predicting the Possible Targets of Ru(II)-Based Complexes as Anticancer Agents

In cancer chemotherapy, metal-based complexes have been recognized as the most promising means of inhibiting cancer growth due to the successful application of cis-platin and its derivatives above many of the existing organic anticancer agents. The limitations in their rational design can be traced to the complexity of the mechanism of their operations, lack of proper knowledge of their targets and lack of force fields in docking packages to appropriately define the metal centre of the organometallic complexes. In this paper, some of the promising anticancer complexes of Ru(II) such as the rapta-based complexes formulated as [Ru(η6-p-cymene)L2(pta)] and those with unusual ligands are considered. CatB and kinases which have been experimentally confirmed as possible targets of the complexes are also predicted by the three methods as one of the most targeted receptors while TopII and HDAC7 are predicted by two and one of the methods as best targets. The interesting features of the binding of the complexes show that some of the complexes preferentially target specific macromolecules than the others, which is an indication of their specificity and possibility of their therapeutic combination without severe side effects that may come from competition for the same target. Also, introduction of unusual ligands is found to significantly improve the activities of most of the complexes studied. Strong correlations are observed for the predicted binding sites and the orientation of the complexes within the binding site by the three methods of docking. However there are disparities in the ranking of the complexes by the three method of docking, especially that of Glide.

Inhibitory activities and possible anticancer targets of Ru(II)-based complexes using computational docking method

In an effort to search for better alternatives to cis-platin and its derivatives that are non-selective cytotoxic anticancer agents, many metal based complexes especially that of Ru(II) that will have alternate targets other than universal target such as DNA have been suggested. This paper focus more on finding an alternative protein targets other DNA for some Ru(II)-based complexes using computational docking as a means of addressing commonly reported research challenges with regards to the lack of proper understanding of the anticancer targets of Ru-based complexes. The observed interactions through our docking studies showed that, besides predicted targets such as CatB, HP-NCP and kinase which is in good agreement with experiment since they have been experimentally suggested as possible target of Ru-based anticancer agents, other targets such as RNR and HDAC7 are proposed. Majority of the complexes on the average showed good interactions with rHA which will most likely enhance their pharmacokinetic properties. There is the possibility of some of them acting as anticancer and as antibacterial agent because they bind more favourably with DNA-Gyrase.

Experimental and theoretical investigation of the spectroscopic and electronic properties of pyrazolyl ligands.

The electronic and spectroscopic properties of seven pyrazole derivatives are presented in order to give a clear understanding of their distinguishing features. Four out of the seven ligands are synthesised and are also characterised experimentally. A very high correlation was observed between the experimental and the theoretical IR, (1)H NMR and (13)C NMR, which help in the characterisation of the ligands. The excitation properties computed using the TDDFT shows that most of experimentally observed absorptions of the ligands are predominantly form either the HOMO or HOMO-1 to LUMO or LUMO+1. The characteristic features of the (*)N atoms (i.e. metal available coordinating centre) shows that the carboxylic unit may possibly decrease the metal affinity of the pyrazole unit while the pyridine unit will increase the affinity. The conductivity properties of the seven ligands are found to be in the order of bdmpzpy>bpzpy>bphpza>bdcpzpy>phpz>dcpz. The J-coupling of (*)NN can give an insight into the variation in their bond distance, bond stretch and bond strength in the ligands. Also the atomic properties of the (*)N atoms and their (*)NN bonds can help in the molecular characterisation, differentiation and in prediction of the non-linear optical properties of the ligands as conductive materials.

Theoretical study of the electronic and spectroscopic properties of some Ru(II) anticancer complexes.

DFT method has been applied to study the thermodynamic and spectroscopic properties of three Ru-based complexes. Possible reasons for the reported experimental stability of complexes 1 and 2 with bidentate chelating ligands over complex 3 have been explained using computed properties. The results show that the trend in their thermodynamic, hyperpolarizabilities, magnetizabilities and the NMR isotropic shielding agree well with many of their experimental properties which give further detail explanation to the reported differences in their stability, hydrolysis and anticancer activities. We also found out that these complexes which were originally designed as anticancer agents have high hyperpolarizabilities which suggest that they can also act as good non-linear optical (NLO) materials.

The Spectroscopic and Conductive Properties of Ru(II) Complexes with Potential Anticancer Properties

Different density functional methods (DFT) have been used to optimize and study the chemistry of five potential anticancer complexes in terms of their electronic, conductive, and spectroscopic properties. Many of the computed properties in addition to the IR and QTAIM analysis of the NMR are dipole moment vector (), linear polarizability tensor (), first hyperpolarizability tensors (), polarizability exaltation index (), and chemical hardness () of the complexes. Stable low energy geometries are obtained using basis set with effective core potential (ECP) approximation but, in the computation of atomic or molecular properties, the metal Ru atom is better treated with higher all electron basis set like DGDZVP. The spectroscopic features like the IR of the metal-ligand bonds and the isotropic NMR shielding tensor of the coordinated atoms are significantly influenced by the chemical environment of the participating atoms. The carboxylic and pyrazole units are found to significantly enhance the polarizabilities and hyperpolarizabilities of the complexes while the chloride only improves the polarity of the complexes. Fermi contacts (FC) have the highest effect followed by the PSO among all the four Ramsey terms which defined the total spin-spin coupling constant J (HZ) of these complexes.

Synthesis of pyrazole derivatives and their spectroscopic properties investigated using both experimental and theoretical approaches

Pyrazoles are unique ligands that have attracted significant research attention due to extensive use of their derivatives in transition metal coordination chemistry. Two pyrazole (pz) derivatives bpzm and bpza were synthesised and their structures are distinguished from the precursor pz using spectroscopic analysis. Many of the functional groups in these ligands are found to be Raman active, which also helps in their spectroscopic elucidation. The electronic, spectroscopic and conductivity properties of pz, bpzm, bpza and bpzpya were further studied using DFT methods. The computed values obtained from techniques such as IR, 1H-NMR, 13C-NMR and UV were found to be highly correlated with the experimental values. Many of the computed properties like the dipole, band gap, hyperpolarizability and reactivity are in the order of bpzpya > bpza > bpzm > pz. The possible application of the ligands can be predicted from the correlation of *N atomic properties with molecular properties of the ligands.

Computational studies of the electronic, conductivities, and spectroscopic properties of hydrolysed Ru(II) anticancer complexes

The mechanism of activation of metal-based anticancer agents was reported to be through hydrolysis. In this study, computational method was used to gain insight to the correlation between the chemistry of the hydrolysis and the anticancer activities of selected Ru(II)-based complexes. Interestingly, we observed that the mechanism of activation by hydrolysis and their consequential anticancer activities is associated with favourable thermodynamic changes, higher hyperpolarizability (β), lower band-gap and higher first-order net current. The Fermi contact (FC) and spin dipole (SD) are found to be the two most significant Ramsey terms that determine the spin-spin couplings (J(HZ)) of most of the existing bonds in the complexes. Many of the computed properties give insights into the change in the chemistry of the complexes due to hydrolysis. Besides strong correlations of the computed properties to the anticancer activities of the complexes, using the quantum theory of atoms in a molecule (QTAIM) to analyse the spectroscopic properties shows a stronger correlation between the spectroscopic properties of Ru atom to the reported anticancer activities than the sum over of the spectroscopic properties of all atoms in the complexes.

Effects of bidentate coordination on the molecular properties rapta-C based complex using theoretical approach

In this work several quantum properties including the NEDA and QTAIM are computed on three models of rapta-C complexes using DFT with hybrid functional and basis set with ECP and without ECP. Several interesting correlations within the observed properties and also with the reported experimental behaviors of these complexes including their biological activities are presented. The study shows that the stability of the two complexes with bidentate ligands is associated with their high hydrogen bonding stability and existence of stronger non-covalent metal-ligand bonds. The energy decomposition analysis indicated that inter-atomic interactions in the three forms of rapta-C complexes and their stability are governed by the charge transfer term with significant contributions from polarization and electrostatic terms. The higher stability of complex 1 and 2 over 3 comes from the lower exchange repulsion and higher polarization contributions to their stability which agrees perfectly with the experimental observation. Our results provide insight into the nature of intramolecular forces that influence the structural stability of the three complexes.

Exploring the Ruthenium-Ligands Bond and Their Relative Properties at Different Computational Methods

We report some experimental bond distances and computational models of six ruthenium bonds obtained from DFT to higher computational methods like MP2 and CCSD. The bonds distances, geometrical RMSD, and the thermodynamic properties of the models from different computational methods are similar. It is observed that optimization of molecules of many light atoms with different functional methods results in significant geometrical variation in the values and order of the computed properties. The values of the hyperpolarizabilities, HOMO, LUMO, and isotropic and anisotropic shielding are found to depend greatly on the type of the functional used and the geometrical variation rather than on the nature of basis set used. However, all the methods rated modelled Ru-S, Ru-Cl, and Ru-O bonds as having the highest hyperpolarizabilities values. The infrared spectra data obtained from the different computational methods are significantly different from each other except for MP2 and CCSD which are found to be very similar.

One and Multiple Bonds Interatomic Spin-Spin Coupling in η6-Cymene Ru(II) of 3,5-Dimethyl-, 3,5-Dicarboxylic-, and 5-Phenyl-pyrazole Derivatives

The changes in the interatomic distances and the corresponding spin-spin coupling as a result of the hydrolysis of the ruthenium complexes and the effects of different derivatives of the pyrazole ligands and the substituents methyl, carboxylic, and phenyl on the pyrazole rings were studied. A good agreement was obtained between the experimental and the theoretical proton NMR. Significant changes are observed in the isotropic and anisotropic shielding tensor of the atoms and related spin-spin coupling of their bonds due to hydrolysis of the complexes. This observation gives more insight into the known mechanism of activation of the ruthenium complexes by hydrolysis. There are no direct effects of interatomic distances on many of the computed spin-spin couplings with the exception of 1J(Ru-N) which shows significant changes especially within the pair of 1J(Ru-N) in the complexes with two nitrogen atoms of the bis-pyrazole moiety. The magnitude of interatomic spin-spin coupling of the Ru-X follows the order of Ru-Cl > Ru-N > Ru-C > Ru-O. The Ramsey term Fermi contact (FC) has the most significant contribution in most of the computed spin-spin interactions except in 1J(Ru-Cl) and 1J() which are predominantly defined by the contribution from the paramagnetic spin orbit (PSO).