A DFT-Based QSAR and Molecular Docking Studies on Potent Anti-Colon Cancer Activity of Pyrazole Derivatives

Abstract: The investigation of the novel hybrid, 1, 2, 3-triazole moiety combined with pyrimidine derivatives against human esophageal carcinoma is an unexplored field of theoretical/computational chemistry. Also, the development of new drugs still remains a major challenge, cost-intensive and time-consuming, thus making the computational approach now a hot topic due to its ability to hasten up and aid the process of drug designs. Here, the use of the quantum chemical method via density functional theory (DFT) was employed in calculating molecular descriptors for developing the quantitative structure-activity relation (QSAR) model which predicts bioactivity of the selected 1, 2, 3-triazole-pyrimidine derivatives. Quantum chemical method implemented in Spartan 14, was used in calculating the molecular descriptors. The obtained results were imputed into Gretl and SPSS (software package for social sciences) to generate a novel QSAR model equation for human esophageal carcinoma (EC-109) through multiple linear regression. The relationship between the experimental and predicted inhibition efficiency (IC50) of 1,2,3-triazole-pyrimidine with EC-109 was calculated which gives good correlation results. QSAR was validated using CV.R2 and R a 2 . Fitting value (R2) of 0.999 with an adjusted fitting value ( R a 2 ) of 0.995 was obtained and the result of validating QSAR performance gave CV.R2 and R a 2 value that is greater than 0.6, signifying its appropriateness and dependability. Molecular docking through simulation using Discovery Studio 4.1, Autodock Tool 1.5.6 and AutodockVina 1.1.2 was also carried out to calculate the free energy of ligand-receptor interactions as well as ligand conformation in the receptor-binding site. The results obtained revealed the presence of hydrogen bond interaction of the ligands with the amino acids residue in the binding sites of the receptor. Conformation of the ligands was essential property for binding ligand with the receptor. Critical examination and the correlations between the IC50 and binding energy showed the activeness of ligand conformation in the gouge of the receptor with binding energy greater than the 5-fluorouracil (5- Fu) that was used as the standard compound.

Abstract: The emergence of new psychoactive substances (NPS) has raised many issues in the context of law enforcement and public drug policies. In this scenario, interdisciplinary studies are crucial to the decision-making process in the field of criminal science. Unfortunately, information about how NPS affect people's health is lacking even though knowledge about the toxic potential of these substances is essential: the more information about these drugs, the greater the possibility of avoiding damage within the scope of a harm reduction policy. Traditional analytical methods may be inaccessible in the field of forensic science because they are relatively expensive and time-consuming. In this sense, less costly and faster in silico methodologies can be useful strategies. In this work, we submitted computer-calculated toxicity values of various amphetamines and cathinones to an unsupervised multivariate analysis, namely Principal Component Analysis (PCA), and to the supervised techniques Soft Independent Modeling of Class Analogy and Partial Least Square-Discriminant Analysis (SIMCA and PLS-DA) to evaluate how these two NPS groups behave. We studied how theoretical and experimental values are correlated by PLS regression. Although experimental data was available for a small amount of molecules, correlation values reproduced literature values. The in silico method efficiently provided information about the drugs. On the basis of our findings, the technical information presented here can be used in decision-making regarding harm reduction policies and help to fulfill the objectives of criminal science.

Abstract: Non-pharmaceutical fentanyls (NPFs) are synthetic substances analogous to fentanyl that have not been approved for medical use. Their clandestine synthesis involves chemical modification of an existing drug, which may cause unpredictable pharmacological effects. New structures are emerging rapidly, and there is a lack of information for characterization. It makes their chemical identification difficult. In this scenario, in silico methods have become an alternative to study these systems. Here, we have applied factorial design to decide the best conditions to perform quantum calculations to obtain the infrared spectra of 46 seized NPFs. A multivariate classification was used to establish the main spectral characteristics of these substances. Similarities between theoretical and experimental spectra were determined through vibrational frequencies comparison, Kullback-Leibler divergence, and SIMCA evaluation. The in silico methods provided valuable information about illegal substances and proved helpful in predict the spectroscopic properties of new fentanyl analogous drugs.

Abstract: Despite the remarkable thermochemical accuracy of Kohn–Sham density‐functional theories with gradient corrections for exchange‐correlation [see, for example, A. D. Becke, J. Chem. Phys. 96, 2155 (1992)], we believe that further improvements are unlikely unless exact‐exchange information is considered. Arguments to support this view are presented, and a semiempirical exchange‐correlation functional containing local‐spin‐density, gradient, and exact‐exchange terms is tested on 56 atomization energies, 42 ionization potentials, 8 proton affinities, and 10 total atomic energies of first‐ and second‐row systems. This functional performs significantly better than previous functionals with gradient corrections only, and fits experimental atomization energies with an impressively small average absolute deviation of 2.4 kcal/mol.

Abstract: A correlation-energy formula due to Colle and Salvetti [Theor. Chim. Acta 37, 329 (1975)], in which the correlation energy density is expressed in terms of the electron density and a Laplacian of the second-order Hartree-Fock density matrix, is restated as a formula involving the density and local kinetic-energy density. On insertion of gradient expansions for the local kinetic-energy density, density-functional formulas for the correlation energy and correlation potential are then obtained. Through numerical calculations on a number of atoms, positive ions, and molecules, of both open- and closed-shell type, it is demonstrated that these formulas, like the original Colle-Salvetti formulas, give correlation energies within a few percent.

Abstract: Cancer as a disease in the human population is becoming a larger health problem, and the medicines used as treatments have clear limitations. In the past 20 years, there has been a tremendous increase in our knowledge of the molecular mechanisms and pathophysiology of human cancer. Many of these mechanisms have been exploited as new targets for drug development in the hope that they will have greater antitumor activity with less toxicity to the patient than is seen with currently used medicines. The fruition of these efforts in the clinic is just now being realized with a few encouraging results.

Abstract: The binding of small molecule ligands to large protein targets is central to numerous biological processes. The accurate prediction of the binding modes between the ligand and protein, (the docking problem) is of fundamental importance in modern structure-based drug design. An overview of current docking techniques is presented with a description of applications including single docking experiments and the virtual screening of databases.