Molecular Docking and In-silico Pharmacokinetic Investigations towards Designing Multi-target Potent Dengue Virus Inhibitors with enhanced Pharmacokinetic Profile

AbstractThe widespread of dengue infection globally has become a great source of concern especially to developing countries with limited resources to control the spread of the dengue virus vector as such infection characterized by fever, joint pain, etc. may progress to a fatal phase such as dengue hemorrhagic fever and organ failure or dengue shock syndrome. An in-silico method using the DFT approach was employed for the geometric optimisation of phthalazinone derivatives with previously established interaction with NS2B-NS3 protease of dengue virus. Herein, molecular docking was employed to evaluate their biochemical interactions with dengue virus serotype 2 protease NS-5 as multi-target. Likewise, the ADME/PK property of the studied compounds was investigated. The molecular docking calculation showed that the previously reported compound 21 with the best potency against NS2B-NS3 protease had the best docking score of -9.0 kcal/mol against NS-5 protease. The physicochemical and ADME/PK properties result revealed that these compounds are orally bioavailable with high gastrointestinal absorption, and are all inhibitors of CYP-3A4 and CYP-2D6 except compound 7 which is a non-inhibitor of CYP-2D6. Also, all the compounds are substrates of P-glycoprotein. The information derived from this study can be utilized in the drug discovery process to improve the anti-dengue activity of the studied compounds. This study would provide physicochemical and pharmacokinetics properties required for the identification of potent anti-dengue drugs and other relevant information in drug discovery

DFT and PM3 Computational Studies of the Reaction Mechanism of the Oxidation of L-Tyrosine by Iodine in the Gas Phase

- The oxidation of L-Tyrosine by molecular iodine was studied using semi-empirical and density functional theory methods. Molecular information such as net charges, values of frontier orbital energies, composition, proportions and bonding contribution were obtained and analyzed. Thus, possible reactive sites were proposed and the reaction mechanism was postulated. The postulated transition states, intermediates and products were also computed using the PM3 and DFT methods. Computed enthalpies of the oxidation reaction at standard conditions for the PM3 and DFT calculation were 216.97 kJ/mol and -36327404.72 kJ/mol respectively. The calculated ΔGo andΔSo, for the transition states according to the DFT model were both large and negative indicating that the processes were exergonic associative substitution reactions

QSAR MODELLING OF SOME ANTICANCER PGI50 ACTIVITY ON HL-60 CELL LINES

QSAR (2D and 3D) studies were performed on a series of CAMPTOTHECIN derivatives using Material Studio software (accelrys). QSAR study performed on 102 analogues of which 90 were used in the training set and the rest 22 considered for the test set.  QSAR study performed using Genetic function approximation (GFA). GFA method came out with good correlation coefficient 0.837 , cross-validated coefficient 0.792  and R2Test of 0.9408. A highly predictive and statistically significant model was generated. The QSAR models were found to accurately predict the anticancer activity of structurally diverse test set compounds and to yield reliable clues for further optimization of the of CAMPTOTHECIN derivatives in the data set

Total phenolic, flavonoid contents and in-vitro anti-inflammation evaluation of ethanol extracts of Hibiscus sabdariffa calyx, Malus domestica and their 1:1 extracts blend on protein denaturation

Hibiscus sabdarifa and Malus domestica are well known and widely used herbs, which contains several interesting bioactive constituents and possesses health promoting properties. The aim of this study is to determine the total phenolic and flavonoid contents, evaluate and compare the anti-inflammatory effects of ethanol extracts of the two extracts and a 1:1 blend of the extracts against the denaturation of proteins in vitro. The respective extracts were analyzed for their contents of polyphenols and flavonoids. The test extracts and reference drug (Ibuprofen) of varying concentrations were also incubated with egg albumin under controlled experimental conditions and subjected to determination of absorbance to assess the anti-inflammatory property. The results obtained exhibited a concentration-dependent inhibition of protein denaturation by both extracts, the 1:1 blend as well as the reference drug. The EC50 for extracts as well as those for the blend and the reference drug were determined by the dose-response curve using Graphpad Prism 5.0 software

PM3 and DFT Computational Studies of the Reaction Mechanism of Formaldehyde and Isoleucine

The reaction of formaldehyde and Isoleucine was studied using semi-empirical and density functional theory methods. Possible reactive sites are proposed and reaction mechanism postulated. It was found that the Isoleucine nitrogen attacks the carbonyl carbon of formaldehyde and forms a methylol intermediate that undergoes a condensation with another Isoleucine to produce a Methylenediisoleucine through a methylene bridge (cross-linking). The enthalpies of the reaction are -78.79 kJ/mol and -39.14kJ/mol for PM3 and DFT respectively also ΔSo and ΔGo, for the PM3 and DFT studies predicted. The reaction was found to be exothermic and second order

A novel QSAR model for designing, evaluating,and predicting the anti-MES activity of new 1H-pyrazole-5-carboxylic acid derivatives

A quantitative structure–activity relationship (QSAR) study was performed to develop a model that relates the structures of 62 compounds, which have activity against maximal electroshock induced seizure (MES), with their anti-MES activity. Molecular structures of the compounds were geometrically optimized and energetically minimized using a combination of modified Merck force field (MMFF) molecular mechanics, Austin model 1 (AM1) semi-empirical quantum mechanical and density functional theory (DFT) quantum mechanical method using the Becke’s three parameter exchange functional (B3) hybrid with Lee, Yang and Parr correlation functional (LYP) and basis set of the double zeta split valence plus polarization quality 6-31G** i.e. B3LYP/6-31G**. Theoretically derived descriptors were obtained from the optimized structures, a genetic function approximation (GFA) algorithm was also applied to select the optimal descriptors and multiple linear regression (MLR) was used to establish a relationship between the anti-MES activity of the compounds and the optimal molecular descriptors. A six-parametric equation containing dipole moment (μ), energy of the lowest unoccupied molecular orbital (ϵLUMO), polar surface area (PSA), accessible surface area derived from wave function (WAA), sum of the square root of square of the charge on all atom of the molecule (QA) and sum of the square root of square of the charge on all fluorine atom in the molecule was obtained as the QSAR model in the present study with good statistical qualities (R2=0.937, R2adj=0.928, F=104.11, R2pred=0.929 and Q2=0.913). The QSAR model was used to study estimate the anti-MES activities of 1H-pyrazole-5-carboxylic acid derivatives not yet synthesized. 10 out of the 101 screened compounds had improved anti-MES activity when compared to the template (i.e. ethyl 4-(4-chlorophenyl)-3-morpholino-1H-pyrrole-2-carboxylate, which is compound number 61 in the dataset) used to design the 101 derivatives. These 10 compounds were docked with voltage-gated sodium channel (PDB code: 2KaV) and there binding affinity were found to were found to be comparable to that of phenytoin (a standard drug known to possess anti-MES activity)