Molecular properties and In silico bioactivity evaluation of (4-fluorophenyl)[5)-3-phen-(4-nitrophenyl yl-4,5-dihydro-1H-pyrazol-1-yl]methanone derivatives: DFT and molecular docking approaches.

Objectives: Molecular structures, spectroscopic properties, charge distributions, frontier orbital energies, nonlinear optical (NLO) properties and molecular docking simulations were analyzed to examine the bio-usefulness of a series of (4-fluorophenyl)[5-(4-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl]methanone derivatives. Methods: The compounds were studied through computational methods. Equilibrium optimization of the compounds was performed at the B3LYP/6-31G(d,p) level of theory, and geometric parameters, frequency vibration, UV-vis spectroscopy and reactivity properties were predicted on the basis of density functional theory (DFT) calculations. Results: The energy gap (ΔEg), electron donating/accepting power (ω-/ω+) and electron density response toward electrophiles/nucleophiles calculated for M1 and M2 revealed the importance of substituent positioning on compound chemical behavior. In addition, ω-/ω+ and ΔEn/ΔEe indicated that M6 is more electrophilic because of the presence of two NO2 groups, which enhanced its NLO properties. The hyperpolarizability (ß0) of the compounds ranged from 5.21 × 10-30 to 7.26 × 10-30 esu and was greater than that of urea; thus, M1-M6 were considered possible candidates for NLO applications. Docking simulation was also performed on the studied compounds and targets (PDB ID: 5ADH and 1RO6), and the calculated binding affinity and non-bonding interactions are reported. Conclusion: The calculated ω- and ω+ indicated the electrophilic nature of the compounds; M6, a compound with two NO2 groups, showed enhanced effects. Molecular electrostatic potential (MEP) analysis indicated that amide and nitro groups on the compounds were centers of electrophilic attacks. The magnitude of the molecular hyperpolarizability suggested that the entire compound had good NLO properties and therefore could be explored as a candidate NLO material. The docking results indicated that these compounds have excellent antioxidant and anti-inflammatory properties.

In Vitro Biological Estimation of 1,2,3-Triazolo[4,5-d]pyrimidine Derivatives as Anti-breast Cancer Agent: DFT, QSAR and Docking Studies.

BACKGROUND & OBJECTIVE: Series of synthesized molecular compounds were considered as anti-breast cancer. The molecular descriptors which describe the microbial activities of the studied compounds were calculated using theoretical approach. METHODS: The calculated parameters obtained EHOMO (eV), ELUMO (eV), dipole moment (Debye), log P, molecular weight (amu), HBA, HBD, Vol and Ovality were screened. The obtained calculated descriptors were used to develop QSAR model for prediction of experimental inhibition concentration (IC50) using SPSS and Gretl software packages for multiple linear regression (MLR) and MATLAB for the artificial neural network (ANN). RESULTS: From this statistical analysis, MLR and ANN were observed to be predictive, however, ANNQSAR model predicted more efficiently than MLR. CONCLUSION: Furthermore, molecular docking study was executed with breast cancer cell line (PDB ID: 1hi7); it was observed that BS20 with binding energy of -7.0 kcal/mol bounded more efficiently than other compounds also, it inhibited more than the standard used (5-FU).

Anti-gastric cancer activity of 1,2,3-triazolo[4,5-d]pyrimidine hybrids (1,2,3-TPH): QSAR and molecular docking approaches.

Gastric cancer as a dreaded disease which occurs in the digestive system of human being remain a threat to the medical world. Bioactivity of series of designed and synthesized molecular compounds containing triazole and pyrimidine moieties were subjected to quantum chemical calculations using B3LYP/6-31+G∗. The calculated molecular descriptors such as the EHOMO (eV), ELUMO (eV), band gap (eV), chemical hardness (η), global nucleophilicity, dipole moment (Debye), chemical potential, log P, molecular weight (amu) and Ovality. The descriptors that describe anti-gastric cancer activity of the studied compounds were used for QSAR analysis using SPSS and Gretl software packages for multiple linear regression (MLR), XLSTAT for partial least square (PLS) and MATLAB for artificial neural network (ANN). The methods (MLR, PLS, and ANN) were predictive. Nevertheless, ANN performed better than MLR and PLS. More so, molecular docking study was executed on the studied compounds and gastric cancer cell line (PDB ID:4oum); the docking studies showed that 2-(1-(2-(3-benzyl-5-(benzylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)hydrazono)ethyl)phenol (A22) having the lowest binding affinity (-8.40 kcal/mol); this was correlated to the observed inhibitory activity of the compound against gastric cancer. Thus, it showed better inhibition than other studied compounds. The amino acid residues that were involved in stabilizing A22 in the active site of the 4oum are: VAL-9, ALA-10, THR-49, ASN-48, PRO-47 and TYR-46. Also, a good relationship was observed between the calculated binding affinity and the observed inhibition concentration (IC50).

In silico studies on the role of mutant Y337A to reactivate tabun inhibited mAChE with K048.

Organophosphorus compound (OP) tabun is resistant to reactivate by many oxime drugs after the formation of OP-conjugate with AChE. The reactivation of tabun-inhibited mAChE and site-directed mutants by bispyridinium oxime, K048 (N-[4-(4-hydroxyiminomethylpyridinio)butyl]-4-carbamoylpyridinium dibromide) showed that the mutations significantly poor the overall reactivation efficacy of K048. We have unravelled the lowered efficacy of K048 with the tabun-mutant mAChE(Y337A) using docking and steered molecular dynamics (SMD) simulations. The computed results showed some interesting features for the interaction of drug molecule K048 with tabun-mAChE(wild-type) and tabun-mutant mAChE(Y337A). The SMD simulations showed that the active pyridinium ring of K048 is directed towards the phosphorus atom conjugated to the active serine (SUN203) of tabun-mAChE(wild-type). The cradle shaped residues Tyr337-Phe338 present in the choline binding site stabilize the active pyridinium ring of K048 with π-π interaction and the residue Trp86 involved in T-shaped cation-π interaction. However, in the case of tabun-mutant mAChE(Y337A).K048 conjugate, the replacement of aromatic Tyr337 with the aliphatic alanine unit in the choline binding site, however, loses one of the π-π interaction between the active pyridinium ring of K048 and the Tyr337. The placement of aliphatic alanine unit resulted in the displacement of the side chain of Phe338 towards the His447. Such displacement is causing the inaccessibility of the drug towards the phosphorus atom conjugated to the active serine (SUN203) of tabun-mutant mAChE(Y337A). Furthermore, the unbinding of the K048 with SMD studies showed that the active pyridinium ring of the drug undergoes a complete turn along the gorge axis and is directed away from the phosphorus atom conjugated to the active serine of the tabun-mutant mAChE(Y337A). Such effects inside the gorge of tabun-mutant mAChE(Y337A) would lower the efficacy of the drug molecule (K048) for the reactivation process. The binding free energy computed for the tabun-mAChE(wild-type) and tabun-mutant mAChE(Y337A) with K048 showed that the drug molecule prefers to bind strongly with the former enzyme (∼30 kJ/mol) than the later one.

Structural and electronic properties of 4H-cyclopenta[2,1-b,3;4-b']dithiophene S-oxide (BTO) derivatives with an S, S=O, O, SiH2, or BH2 bridge: semi-empirical and DFT study.

In this paper, we theoretically studied the geometries, stabilities, and the electronic and thermodynamic properties of 4H-cyclopenta[2,1-b,3;4-b']dithiopene S-oxide derivatives (BTO-X, with X = BH(2), SiH(2), S, S=O, or O) using semi-empirical methods, ab initio methods, and density functional theory. The geometries and thermodynamic parameters calculated by PM3 were in good agreement with those calculated with B3LYP/6-31 G*. The band gap calculated using B3LYP/6-31 G* ranged from 3.94 eV (BTO-O) to 3.16 eV (BTO-B). The absorption λ(max) calculated using B3LYP/6-31 G* was shifted to longer wavelengths when X = BH(2), SiH(2), or S=O (due to their electron-withdrawing effects) and to shorter wavelengths for BTO-S and BTO-O as compared to the λ(max) for the thiophene S-oxide (2TO) dimer. The changes in ΔH°, ΔS°, and ΔG° calculated using both semi-empirical and DFT methods were quite similar.