Sathya Babu

Computational Analysis of CRTh2 receptor antagonist

CRTh2 receptor is an important mediator of inflammatory effects and has attracted much attention as a therapeutic target for the treatment of conditions such as asthma, COPD, allergic rhinitis and atopic dermatitis. In pursuit of better CRTh2 receptor antagonist agents, 3D-QSAR studies were performed on a series of 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl) acetic acids. There is no crystal structure information available on this protein; hence in this work, ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed by atom by atom matching alignment using systematic search and simulated annealing methods. The 3D-QSAR models were generated with 10 different combinations of test and training set molecules, since the robustness and predictive ability of the model is very important. We have generated 20 models for CoMFA and 100 models for CoMSIA based on two different alignments. Each model was validated with statistical cut off values such as q(2)>0.4, r(2)>0.5 and r(2)pred>0.5. Based on better q(2) and r(2)pred values, the best predictions were obtained for the CoMFA (model 5 q(2)=0.488, r(2)pred=0.732), and CoMSIA (model 45 q(2)=0.525, r(2)pred=0.883) from systematic search conformation alignment. The high correlation between the cross-validated/predicted and experimental activities of a test set revealed that the CoMFA and CoMSIA models were robust. Statistical parameters from the generated QSAR models indicated the data is well fitted and have high predictive ability. The generated models suggest that steric, electrostatic, hydrophobic, H-bond donor and acceptor parameters are important for activity. Our study serves as a guide for further experimental investigations on the synthesis of new CRTh2 antagonist.

3D-QSAR studies on indole and 7-azoindole derivatives as ROCK-2 inhibitors: An integrative computational approach

Rho Kinases (ROCK) has been found to regulate a wide range of fundamental cell functions such as contraction, motility, proliferation, and apoptosis. Recent experiments have defined new functions of ROCKs in cells, including centrosome positioning and cell-size regulation, which might contribute to various physiological and pathological states. In this study, we have performed pharmacophore modeling and 3D QSAR studies on a series of 36 indoles and 7-azoindoles derivatives as ROCK2 inhibitors to elucidate the structural variations with their inhibitory activities. Ligand based CoMFA and CoMSIA models were generated based on three different alignment methods such as systematic search, simulated annealing and pharmacophore. A total of 15 CoMFA models and 27 CoMSIA were generated using different alignments. One model from each alignment is selected based on the statistical values. Contour maps of the selected models were compared, analysed and reported. The 3D QSAR study revealed that electro positive group linked to the methoxy-benzene ring position of the structure will enhance the biological activity and bulkier substitutions are preferred in the methyl dihydroindole region. Also, it is found that the hydrogen bond donor substituted at the R1 position enhances the inhibitory activity. In future, this study would give proper guidelines to further enhance the activity of novel inhibitors for ROCK2.

Molecular Modeling Study on Diazine Indole Acetic Acid Derivatives for CRTH2 Inhibitory Activity

In the present work, molecular modeling studies have been reported on a series of diazine indole acetic acid derivatives to analyze the structure-activity relationship studies of CRTH2 using fragment (Topomer CoMFA and HQSAR) and field (CoMFA and CoMSIA) based QSAR methods. Twenty-six compounds were used as a training set to establish the model, and six compounds were used as a test set to validate the model. The generated models exhibited good statistical results such as correlation coefficient (r2) and the cross-validated correlation coefficient (q2). Topomer CoMFA analysis yielded the q2 of 0.610 and r2 of 0.981. HQSAR model generated using bond and connectivity as fragment distinction and 3-6 as fragment size has the q2 value of 0.707 and conventional r2 value of 0.892 with five components. CoMFA model was assessed by cross-validated q2 value of 0.543 and r2 value of 0.901 with steric and electrostatic fields. CoMSIA model generated using steric, hydrophobic and donor fields with q2 value of 0.550 and r2 value of 0.888 was found to be the optimal model among the various models generated. The contour maps were generated to analyze the important structural features that regulate their inhibitory potency. From the result of contour maps we have suggested the critical sites for chemical modification which will be useful in designing potent compounds with improved activity.

Towards a better understanding of the interaction between Somatostatin receptor 2 (SSTR2) and its ligands: a structural characterization study using molecular dynamics and conceptual Density Functional Theory (DFT)

Abstract This study is a part of the extensive research intending to provide the structural insights on somatostatin and its receptor. Herein, we have studied the structural complexity involved in the binding of somatostatin receptor 2 (SSTR2) with its agonists and antagonist. A 3D QSAR study based on comparative molecular field analysis and comparative molecular similarity analysis (CoMSIA) discerned that a SSTR2 ligand with electronegative, less-bulkier, and hydrogen atom donating/accepting substitutions is important for their biological activity. A conceptual density functional theory (DFT) study was followed to study the chemical behavior of the ligands based on the molecular descriptors derived using the Fukui’s molecular orbital theory. We have performed molecular dynamics simulations of receptor–ligand complexes for 100 ns to analyze the dynamic stability of the backbone Cα atoms of the receptor and strength and approachability of the receptor–ligand complex. The findings of this study could be efficacious in the further studies understanding intricate structural features of the somatostatin receptors and in discovering novel subtype-specific ligands with higher affinity. Communicated by Ramaswamy H. Sarma

Theoretical analysis of somatostatin receptor 5 with antagonists and agonists for the treatment of neuroendocrine tumors

We report on SSTR5 receptor modeling and its interaction with reported antagonist and agonist molecules. Modeling of the SSTR5 receptor was carried out using multiple templates with the aim of improving the precision of the generated models. The selective SSTR5 antagonists, agonists and native somatostatin SRIF-14 were employed to propose the binding site of SSTR5 and to identify the critical residues involved in the interaction of the receptor with other molecules. Residues Q2.63, D3.32, Q3.36, C186, Y7.34 and Y7.42 were found to be highly significant for their strong interaction with the receptor. SSTR5 antagonists were utilized to perform a 3D quantitative structure–activity relationship study. A comparative molecular field analysis (CoMFA) was conducted using two different alignment schemes, namely the ligand-based and receptor-based alignment methods. The best statistical results were obtained for ligand-based (

Homology Modeling of Cysteinyl Leukotriene1 Receptor

{q}^{2} = 0.454

Pharmacophore Based Comparative Molecular Field Analysis of CRTh2 Antagonists

q2=0.454,