F. A. Pasha

Pharmacophore and docking-based combined in-silico study of KDR inhibitors

The growth and metastasis of solid tumors is dependent on angiogenesis. The vascular endothelial growth factor (VEGF) and its cell surface receptor in human KDR (kinase domain containing receptor or VEGFR-2) have particular interest because of their importance in angiogenesis. The development of novel inhibitors of VEGFR-2 would be helpful to check the growth of tumors. Quantitative structure activity relationship (QSAR) analyses used to understand the structural factors affecting inhibitory potency of thiazole-substituted pyrazolone derivatives. Several pharmacophore-based models indicated the importance of steric, hydrophobic and hydrogen bond acceptor groups to inhibitory activity. The comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analyses (CoMSIA) based 3D-QSAR models were derived using pharmacophore-based alignment. Both CoMFA (q(2)=0.70, r(2)=0.97 and r(predictive)(2)=0.61) and CoMSIA (q(2)=0.54, r(2)=0.82 and r(predictive)(2)=0.66) gave reasonable results. The molecular docking (receptor-guided technique) with a recently reported receptor structure (PDB=1YWN) were performed. The docked alignment was subsequently used for 3D-QSAR (CoMFA; q(2)=0.56, r(2)=0.97, r(predictive)(2)=0.82, CoMSIA; q(2)=0.58 r(2)=0.91, r(predictive)(2)=0.69). The overall both studies were indicated, steric, electrostatic and hydrogen bond acceptor effects contribute to the inhibitory activity. CoMFA and CoMSIA models suggested that a positive bulk with hydrophobic effect is desirable around position 4 and 5 and hydrogen bond acceptor groups around pyrazolones ring will be helpful.

Elucidation of binding mode and three dimensional quantitative structure-activity relationship studies of a novel series of protein kinase B/Akt inhibitors

Protein kinase B (PKB; also known as Akt kinase) is located downstream in the PI-3 kinase pathway. Overexpression and constitutive activation of PKB/Akt leads to human prostate, breast and ovarian carcinomas. A series of 69 PKB/Akt inhibitors were examined to explore their binding modes using FlexX, and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed to provide structural insights into these compounds. CoMFA produced statistically significant results, with cross-validated q2 and non-cross validated correlation r2 coefficients of 0.53 and 0.95, respectively. For CoMSIA, steric, hydrophobic and hydrogen bond acceptor fields jointly yielded ‘leave one out’ q2 = 0.51 and r2 = 0.84. The predictive power of CoMFA and CoMSIA was determined using a test set of 13 molecules, which gave correlation coefficients,

Quantum chemical QSAR study of flavones and their radical-scavenging activity

r_{{\text{predictive}}}^2

Quantitative structure activity relationship (QSAR) study of estrogen derivatives based on descriptors of energy and softness.

of 0.58 and 0.62, respectively. Molecular docking revealed that the binding modes of these molecules in the ATP binding sites of the Akt kinase domain were very similar to those of the co-crystallized ligand. The information obtained from 3D contour maps will allow the design of more potent and selective Akt kinase inhibitors.

Research Article: Quantitative Structure Activity Relationship (QSAR) Study of Estrogen Derivatives Based on Descriptors of Energy and Softness

Protein kinase CK2, also known as casein kinase‐2, has been found to be involved in cell growth, proliferation and suppression of apoptosis, which is related to human cancers. The series of compounds were identified as casein kinase‐2 inhibitors and their inhibitory activities are a function of a variation of their structures. The current study deals with the pharmacophore identification and, accordingly, the three‐dimensional quantitative structure–activity relationship model development using Pharmacophore Alignment and Scoring Engine. Several hypotheses were developed for the molecular alignments. On the basis of statistical values, the best‐fitted model was identified and the same alignment was used for 3D‐QSAR using comparative molecular field analysis/comparative molecular similarity index analysis. Both the CoMFA (R 2CV = 0.58, R 2 = 0.82 and r 2pred = 0.62) and the comparative molecular similarity index analysis (R 2CV = 0.74, R 2 = 0.98 and r 2pred = 0.81) gave reasonable results. Besides pharmacophore‐based alignment, the maximum common substructure‐based alignment was also used for the comparative molecular field analysis and comparative molecular similarity index analysis. The pharmacophore‐based alignment was more prominent and it has provided important information for the modelling of potent inhibitors. The overall study implies that a highly positive and bulky group with H‐bond donating property is desirable around the nitrogen atom adjacent to the pyrrolidine ring.

Structural studies of B-type Aurora kinase inhibitors using computational methods

AbstractFlavonoid antioxidants act as scavengers of free radicals by rapid donation of a hydrogen atom. This quantitative structure–activity relationship (QSAR) study of flavones was carried by using selected quantum chemical descriptors. PM3 calculations performed by MOPAC 2000 associated with Cache pro. Molecular weight, dielectric energy (kcal/mole), total energy (Hartree), heat of formation (kcal/mole), highest unoccupied molecular orbital (HOMO) energy (eV), lowest unoccupied molecular orbital (LUMO) energy (eV), log P, molar refractivity (MR), hardness (η), softness (S), chemical potential (μ), electrophilicity index (ω), etc. were tested as descriptors, and various QSAR models were constructed. The best-fit model (

In silico quantitative structure-toxicity relationship study of aromatic nitro compounds.

r^{{\text{2}}}_{{{\text{CV}}}} = 0.92,r^{2} = 0.96