Steric Field Descriptors Research Articles

Insights into the key structural features of triazolothienopyrimidines as anti-HIV agents using QSAR, molecular docking, and pharmacophore modeling

The development of severe drug resistance caused by the extensive use of anti-HIV agents has resulted in resistance mutation that compromise efficacy of anti-retroviral. We have selected triazolothienopyrimidine derivatives for our study since these derivatives have potentially inhibited HIV-1 replication. The objectives of our study were to identify the important pharmacophoric features and correlate 3D chemical structure of of triazolothienopyrimidines and predict their anti-HIV activity using 2D-, 3D-QSAR, pharmacophore modeling, and docking studies to explore their binding to HIV-1 reverse transcriptase. Partial least square and k-nearest neighbor methodology were used to develop 2D-QSAR and 3D-QSAR models. The statistical significance of developed QSAR models was checked by internal and external validation. The developed 2D-QSAR model indicated that a significance of presence of electron withdrawing groups, number of hydrogen bond acceptor, Z component dipole moment, and the moment of inertia at X axis of the compounds on their anti-HIV potential. 3D-QSAR results indicated the influence of electrostatic and steric field descriptors in the anti-HIV potential of triazolothienopyrimidines. The pharmacophore mapping represented the importance of aromatic and hydrogen bond acceptor features of compounds to interact with the target. Docking studies revealed that the binding of the triazolothienopyrimidines to HIV-1 reverse transcriptase involved extensive hydrophobic and polar interactions. Collectively, the results of QSAR, pharmacophore mapping, and the docking studies provide an insight into the understanding of the relationship between triazolothienopyrimidines and anti-HIV activity, which may assist in designing new triazolothienopyrimidines with enhanced HIV-1 reverse transcriptase inhibitory and anti-HIV activity.

QSAR and Pharmacophore Mapping Studies on Benzothiazinimines to Relate their Structural Features with anti-HIV Activity.

The development of severe drug resistance caused by the extensive use of anti-HIV agents has resulted in a greatly extensive reduction in these drugs efficacy. To identify the important pharmacophoric features and correlate 3D chemical structure of benzothiazinimines with their anti-HIV potential using 2D, 3D-QSAR and pharmacophore modeling studies. QSAR and pharmacophore mapping studies have been used to relate structural features. 2D QSAR and 3D QSAR studies were performed using partial least square and k-nearest neighbor methodology, coupled with various feature selection methods, viz. stepwise, genetic algorithm, and simulated annealing, to derive QSAR models which were further validated for statistical significance. The physicochemical descriptor XAHydrophilicArea and SsOHE-index, and alignmentindependent descriptor T_C_Cl_6 showed significant correlation with the anti-HIV activity of benzothiazinimines in 2D QSAR. 3D QSAR results showed the significant effect of electrostatic and steric field descriptors in the anti-HIV potential of benzothiazinimines. The generated pharmacophore hypothesis demonstrated the importance of aromaticity and hydrogen bond acceptors. The significant models obtained in this study suggested that these techniques could be used as a guidance for designing new benzothiazinimines with enhanced anti-HIV potential.

Rational design and synthesis of new tetralin-sulfonamide derivatives as potent anti-diabetics and DPP-4 inhibitors: 2D & 3D QSAR, in vivo radiolabeling and bio distribution studies

Type 2 diabetes (T2D) is a severe disease and it is one of the most raising problems worldwide. This study deals with design, synthesis and in vivo determination of a new set of tetralin-sulfonamide derivatives as anti-diabetic and dipeptidyl peptidase-IV (DPP-4) inhibiting agents. Most of the new compounds exhibited significant hypoglycemic effect alongside with DPP-4 suppression potency considering sitagliptin as a reference drug. The most promising compounds 4, 15 showed 2.80 nM DPP-4 IC50 with 20–40 folds selectivity over DPP-8 and DPP-9. 2D and 3D QSAR models were performed using auto QSAR of Schrödinger, QuaSAR of MOE and 3D Field-based QSAR of Schrödinger, respectively. The experimental results revealed that the alignment-independent descriptors, electrostatic and steric field descriptors were significantly correlated with the antidiabetic activity of the new derivatives. In addition, the new compounds were docked in the active site of DPP-4 in reference to sitagliptin to rationalize the binding modes of the compounds with the amino acid residues of the enzyme. Furthermore, 131I-compound 4 complex was selected to evaluate the pharmacokinetic behavioral profile of compound 4 and its body organs uptakes alongside its elimination pathway as a representative example for the rest of the analogues. The bio distribution pattern of the tracer proved the selective accumulation of 131I-substrate in the pancreas and rapid clearance from most of the body organs.

Exploring the structure–activity relationship of oxazolidinones as HIV-1 protease inhibitors—QSAR and pharmacophore modelling studies

In the present study, 2D QSAR and 3D QSAR models and pharmacophore hypothesis were evaluated for a series of N-aryl-oxazolidinone-5-carboxamides to predict their HIV-1 protease inhibitory activity. The developed QSAR models were validated by external validation method, leave-one-out and leave-many-outcross validation, Y-randomization method and applicability domain analysis. The primary findings of this study were that the number of carbon atoms separated from any specific carbon atom by 2- and 7-bond distances, and the number of fluorine atoms separated from any specific fluorine atom by a 5-bond distance in a molecule, altered the compounds' inhibitory action on HIV-1 protease. Further, 3D QSAR study results indicated that the presence of electrostatic and steric field descriptors in N-aryl-oxazolidinone-5-carboxamides significantly inhibited HIV-1 protease. The generated pharmacophore hypothesis of the compounds indicated the significance of the two aromatic and three hydrogen bond acceptor features on HIV-1 protease's inhibitory activity. The proposed model also provided a better understanding of HIV-1 protease's inhibitory activity on oxazolidinones and could be used as guidance for the proposition of new anti-HIV agents.

Exploring QSAR studies on 4-substituted quinazoline derivatives as antimalarial compounds for the development of predictive models

Quantitative structure activity relationship (QSAR) model for antimalarial activity was developed from a set of 51 substituted quinazolines that exhibited remarkable in vitro activity against sensitive and multidrug-resistant Plasmodium falciparum malaria. 2D-QSAR was done using partial least squares method coupled with stepwise variable selection; subsequently, 3D-QSAR was carried out using stepwise variable selection k-nearest neighbor molecular field analysis (kNNMF) approach. Leave-one-out cross-validated correlation coefficient (q2) of 0.7601 and a predicted r2 for the external test (pred_r2) of 0.7108 were obtained with 3D QSAR. Experimental results revealed that the molecular weight, alignment-independent descriptors, electrostatic and steric field descriptors were significantly correlated with antimalarial activity of quinazoline derivatives. The results helped to understand the nature of substituents around quinazoline nucleus, thereby providing new guidelines for the design of novel antimalarials.

Designing hypothesis of diaryl pyrimidine analogs as anti-HIV agent: QSAR approach

Two-dimensional QSAR models were produced by stepwise multiple-linear regression and 3D QSAR models were developed by k-nearest neighbor-molecular field analysis on a database consists of 18 diaryl pyrimidine analogs. The developed QSAR model was evaluated for statistical significance and predictive power. The key conclusion of this study is that the electro-topological state indices for number of carbon atom connected with one double and two single bonds, retention index (fourth order), electrostatic, hydrophobic, and steric field descriptors are significantly affect the anti-HIV activity of diaryl pyrimidine analogs. The selected descriptors serve as a first guideline for the design of novel and potent diaryl pyrimidine analogs as anti-HIV agents. In the present study, we discussed the role of retention index (fourth order), electrostatic, hydrophobic and steric field descriptors in the anti-HIV activity of diaryl pyrimidine analogues.

Synthesis, In Vitro Antitubercular Activity and 3D‐QSAR of Novel Quinoxaline Derivatives

Twenty new quinoxalines bearing azetidinone and thiazolidinone groups were synthesized by cyclocondensation of Schiff bases of quinoxaline-2, 3-dione and were characterized with several analytical tools. They were tested against Mycobacterium tuberculosis H37Rv at a concentration of 10 μg/mL by Microplate Alamar Blue Assay method. Quinoxaline derivatives with 2-chloro, dimethylamino and nitro substitutions exhibited in vitro activity, comparable to that of the drug, isoniazid. Three-dimensional quantitative structure-activity relationship studies indicated that electrostatic and steric field descriptors could explain the observed activity. The developed model fits the data well and has good predictive capability (r² = 0.81, q² = 0.71, F = 27.06, r² _pred = 0.84, r²(m) = 0.84, r² BS = 0.80). Electronegative groups play an important role in the antitubercular activity.

Designing hypothesis of substituted benzoxazinones as HIV-1 reverse transcriptase inhibitors: QSAR approach

A linear quantitative structure activity relationship (QSAR) model is presented for predicting human immunodeficiency virus-1 (HIV-1) reverse transcriptase enzyme inhibition. The 2D QSAR and 3D-QSAR models were developed by stepwise multiple linear regression, partial least square (PLS) regression and k-nearest neighbor-molecular field analysis, PLS regression, respectively using a database consisting of 33 recently discovered benzoxazinones. The primary findings of this study is that the number of hydrogen atoms, number of (−NH2) group connected with solitary single bond alters the inhibition of HIV-1 reverse transcriptase. Further, presence of electrostatic, hydrophobic and steric field descriptors significantly affects the ability of benzoxazinone derivatives to inhibit HIV-1 reverse transcriptase. The selected descriptors could serve as a primer for the design of novel and potent antagonists of HIV-1 reverse transcriptase.

Comparative molecular field analysis of quinine derivatives used as chiral selectors in liquid chromatography: 3D QSAR for the purposes of molecular design of chiral stationary phases

A comparative molecular field analysis (CoMFA) was carried out on a set of aligned quinine-based stationary phase molecules used in enantioselective chromatography. The best QSAR derived has a cross-validated (predictive) r(2)(cv) = 0.671 and a normal r(2) = 0.998. For CoMFAs using both steric and electrostatic fields as descriptors, the steric field descriptors explained more than 91% of the variance while the electrostatic descriptors explained less than 9% of the variance. It is concluded that the long-range electrostatic potential surrounding the positively charged CSPs are not enantiodiscriminating, while the van der Waals and local electrostatic surface features of these CSPs are highly discriminating. Quantum mechanical calculations back up this claim by showing a relatively symmetric electrostatic iso-contour surface. From the QSAR derived here, a region around the carbamate moiety was located where placement of steric bulk is predicted to enhance chiral discrimination. A set of possible synthetic target molecules is presented.

Solid-State and Solution Structure of the Salinomycin−Sodium Complex: Stabilization of Different Conformers for an Ionophore in Different Environments

The conformation of the ionophore−metal complex between salinomycin and sodium was determined in solid state and in solution using X-ray single-crystal structure analysis and a combined approach of 2D-NMR spectroscopy with restrained simulated annealing calculations. The solution structure of the salinomycin−Na complex was studied in two different solvents (DMSO-d6 and CDCl3) in order to focus on conformational differences in various molecular environments. The X-ray structure of the complexed salinomycin is characterized by two separate conformers found in the asymmetric unit with a similar coordination of the central sodium ion buried in the interior, hydrophilic region of this ionophore. A quasi-macrocyclic core structure is stabilized by numerous metal−oxygen electrostatic interactions and by an intramolecular head-to-tail hydrogen bond. The NMR structure in CDCl3 is very similar to those two conformations in the solid state, while the structure in DMSO differs significantly. It could be demonstrated that previously published NMR data in CDCl3 do not define a unique conformational state with sufficient accuracy, while this was possible using our own NMR derived datasets discussed herein. For conformer classification and comparison, steric field descriptors based on the CoMFA methodology are used in conjunction with a principal component analysis to uncover the most relevant structural differences between individual salinomycin−Na structures. These studies provided insight into the specific requirements of metal binding for this important polyether ionophore, which could serve as a model system for studying ion transport across biological membranes. Different environments tend to stabilize different conformations of the outer sphere, while the complexation pattern and the geometry of the coordination sphere of the sodium ion remains unaffected.