In silico Studies of some potential anti-cancer agents on M19-MEL cell line

The resistance of melanoma cancer cells to the known treatments has become a barrier to the success of chemotherapy.  In this research, a quantitative evaluation of the structure-activity relationship (QSAR) was carried out on 57 anti-cancer compounds and some selected potent compounds were screened through Lipinski’s rule and docked. Genetic function algorithm (GFA) was adopted in variables selection and Multiple linear regression (MLR) was used to generate the model. The built QSAR model showed good statistical parameters (( (0.904),  (0.885), Q2cv (0.873) and  (0.779)). The cR⁠2⁠P for Y-randomization is 0.749 and the applicability domain was also determined. The predictive ability of the model was found to be satisfactory and could be used to predict the anti-cancer activity of compounds on M19 MEL cell line. 4 most potent compounds were selected among the data set and screened through Lipinski's rule of five filters for oral bioavailability, ADMET risk filter for a drug like features. Later, V600E-BRAF, a known melanoma cancer target was used for docking. Based on the interaction energy and types of interactions involved, the selected compounds were identified as the best hits against V600E-BRAF. This research would help in the lead identification and design of novel drugs

QSAR modeling of some anticonvulsant molecules as γ-aminobutyrate-aminotransferase inhibitors

Abstract Quantitative structure-activity relationship study was done on 62 compounds with anticonvulsant activity in maximal electroshock-induced seizures test. The molecular structure of the compounds was optimized with parametric semi-empirical PM3 method available in Spartan 14 software. Quantum mechanical descriptors were extracted from the property and output module of the software. Combination of activity based-clustering and genetic function algorithm chemo-metric techniques were used to map molecular descriptors to activity values. A well-validated and robust quantitative structure-activity model was obtained with R2 = 0.947, Q2= 0.924, F = 91.42 and R2pred(test) = 0.881. The descriptor contained in the model suggested an increase in the number of O and N atoms in the molecule augments the activity of the studied compounds. Also, the introduction of electron donating substituents is beneficial to the activity of the studied compounds. Armed with these, information, new hypothetical1H-pyrazole-5-carboxylic acid derivatives were designed using template approach and screened in silico. Compounds with hypothetic anticonvulsant activity better than the template were docked with γ-aminobutyrate-aminotransferase and their binding affinity was found to be comparable and even superior to that of 4-aminohex-5-enoic acid (vigabatrin), a known inhibitor of γ-aminobutyrate-aminotransferase

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

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

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

Molecular modelling and design of lubricant additives and their molecular dynamic simulations studies of Diamond-Like-Carbon (DLC) and steel surface coating

Quantitative Structure–Properties Relationship (QSPR) analysis was carried out on 30 lubricant additives while molecular dynamics simulations study was also performed to determine the dynamic binding strength between the hydrogen-containing DLC (a-C: H) sliding interface and lubricant additives. Reliable and predictable QSPR model was generated along with statistical parameters such as internal and external validations parameters such as squared correlation coefficient R2 (0.807208), adjusted squared correlation coefficient R2adj (0.763674), cross-validation coefficient Q2 (0.68867) and the external validation R2ext (0.6297). Two multifunctional lubricant additives were designed and they were found to have excellent anti-wear properties of 5.295 and 5.192(mm) which were better than the commercially sold lubricating oil additives, ZDDP. In addition, due to the absence of phosphorous and zinc in the molecular structures of the newly designed additives, these additives will not inhibit/limit the activity of the catalytic converter and will not form suspension or particulate matter in the car exhaust pipe. Moreover, the molecular dynamics simulation study revealed that one of the two designed lubricant additives of Benzothiazole derivatives were found to have excellent dynamic binding energies of 466.808 and 470.023 kcal/mol on DLC coating surfaces, while the second designed additive also generated better dynamic binding energies of 266.416 and 157.198 kcal/mol on steel coating surfaces than the commercially sold lubricant additive, ZDDP. This investigation will help in rational synthesis of new and better selective lubricant additives with predetermined dynamic binding energy and provides valuable information for the understanding of dynamic binding energy of additive on DLC and steel coating sliding surfaces. Keywords: QSPR, Lubricant additive, Diamond-Like-Carbon (DLC), Steel, Molecular dynamic simulations, Molecular desig

Computer aided design of novel antibiotic drug candidate against multidrug resistant strains of Salmonella typhi from pyridine-substituted coumarins

Abstract Background The rising cases of resistance to existing antibiotics by Salmonella typhi, has made the development of novel drug candidates a necessity. In this study, a data set of antibacterial pyridine substituted coumarins were subjected to Virtual Screening against SipA effector protein of the bacterium. The compounds were geometry-optimized using Semi-empirical (pm3) method in Spartan 14 software, docked against the active sites of SipA using AutoDock Vina software. The molecule with the best docked score was selected as template and subjected to structural modifications leading to the design of a novel coumarin based drug candidate codenamed Y-1. Results The docking of Y-1 against SipA revealed that it binds to the target with ΔG value of − 9.1 kcal/mol. This value is better than − 6.8 kcal/mol obtained for ciprofloxacin used herein for quality assurance. Additionally, quantum mechanical calculations on Y-1 using DFT (B3LYP/6-31G* basis set) shows a wide energy gap of 3.44 eV and ω value of 1.47 eV, indicating its sound kinetic and thermodynamic stabilities. Y-1 was also found to possess good oral bioavailability and positive pharmacokinetic profiles. Conclusion This is the first time coumarin derivatives are screened against an effector protein of Salmonella typhi. It is envisaged that the findings of this research will provide an excellent blueprint toward the development of novel antibiotics against Salmonella typhi