Receptor-independent 4D-QSAR analysis of a set of norstatine derived inhibitors of HIV-1 protease

A training set of 27 norstatine derived inhibitors of HIV-1 protease, based on the 3(S)-amino-2(S)-hydroxyl-4-phenylbutanoic acid core (AHPBA), for which the -log IC(50) values were measured, was used to construct 4D-QSAR models. Five unique RI-4D-QSAR models, from two different alignments, were identified (q(2) = 0.86-0.95). These five models were used to map the atom type morphology of the lining of the inhibitor binding site at the HIV protease receptor site as well as predict the inhibition potencies of seven test set compounds for model validation. The five models, overall, predict the -log IC(50) activity values for the test set compounds in a manner consistent with their q(2) values. The models also correctly identify the hydrophobic nature of the HIV protease receptor site, and inferences are made as to further structural modifications to improve the potency of the AHPBA inhibitors of HIV protease. The finding of five unique, and nearly statistically equivalent, RI-4D-QSAR models for the training set demonstrates that there can be more than one way to fit structure-activity data even within a given QSAR methodology. This set of unique, equally good individual models is referred to as the manifold model.     

Quantitative structure-based design: formalism and application of receptor-dependent RD-4D-QSAR analysis to a set of glucose analogue inhibitors of glycogen phosphorylase

A method for performing quantitative structure-based design has been developed by extending the current receptor-independent RI-4D-QSAR methodology to include receptor geometry. The resultant receptor-dependent RD-4D-QSAR approach employs a novel receptor-pruning technique to permit effective processing of ligands with the lining of the binding site wrapped about them. Data reduction, QSAR model construction, and identification of possible pharmacophore sites are achieved by a three-step statistical analysis consisting of genetic algorithm optimization followed by backward elimination multidimensional regression and ending with another genetic algorithm optimization. The RD-4D-QSAR method is applied to a series of glucose inhibitors of glycogen phosphorylase b, GPb. The statistical quality of the best RI- and RD-4D-QSAR models are about the same. However, the predictivity of the RD- model is quite superior to that of the RI-4D-QSAR model for a test set. The superior predictive performance of the RD- model is due to its dependence on receptor geometry. There is a unique induced-fit between each inhibitor and the GPb binding site. This induced-fit results in the side chain of Asn-284 serving as both a hydrogen bond acceptor and donor site depending upon inhibitor structure. The RD-4D-QSAR model strongly suggests that quantitative structure-based design cannot be successful unless the receptor is allowed to be completely flexible.     

A simple clustering technique to improve QSAR model selection and predictivity: application to a receptor independent 4D-QSAR analysis of cyclic urea derived inhibitors of HIV-1 protease

A training set of 50 tetrahydropyrimidine-2-one based inhibitors of HIV-1 protease, for which the -log K(i) values were measured, was used to construct receptor independent 4D-QSAR models. A novel clustering technique was employed to facilitate and improve model selection as well as test set predictions. Following the manifold model theory, five unique models were chosen by the clustering algorithm (q(2) = 0.81-0.84). The models were used to map the atom type morphology of the inhibitor binding site of HIV-1 protease as well as to predict the potencies (-log K(i)) of 10 test set compounds. The rank-difference correlation coefficient was used to evaluate the quality of the test set predictions, which was improved from 0.39 to 0.68 when the clustering technique was applied. The set of five models, collectively, identify the important binding characteristics of the HIV protease receptor site. This study demonstrates that the selected simple clustering technique provides a discrete algorithm for model selection, as well as improving the quality of test set, or unknown, compound prediction as determined by the rank-difference correlation coefficient.     

Comparison of azacyclic urea A-98881 as HIV-1 protease inhibitor with cage dimeric N-benzyl 4-(4-methoxyphenyl)-1,4- dihydropyridine as representative of a novel class of HIV-1 protease inhibitors: A molecular modeling study

The functional groups of cage dimeric N-alkyl substituted 3,5-bis(hydroxymethyl)-4-(4-methoxyphenyl)-1,4-dihydropyridines are similar to those of cyclic and azacyclic ureas that are potent inhibitors of HIV-1 protease of the dihydroxyethylene- and hydroxyethylene type, respectively. In the following study the conformity of common functional groups is investigated concerning their orientation in space as well as in the enzyme HIV-1 protease. Starting from X-ray crystal data of the centrosymmetric cage dimeric N-benzyl derivative with ester groups, the derivative with hydroxymethylene groups was built and a systematic conformational search was performed for the conformationally important torsion angles considering electrostatic and van der Waals interactions. From the huge number of conformations those comprising centrosymmetrical and C2-symmetrical energy minima were selected and minimized. The three remaining conformers were fitted to the azacyclic urea A-98881 selected from the HIV-1 protease enzyme- inhibitor complex using the centroids of the corresponding aromatic residues and additionally by the field fit option of the Advanced CoMFA module of SYBYL. Interestingly, the energetically most favourable one, which, additionally, possesses C2-symmetry like the active site cavity of HIV-1 protease, showed the best fit. Comparing the electrostatic potential (EP) of the latter with the EP of A-98881 the aromatic residues show excellent accordance. Slight differences in the extent of the EP were found in the areas of the hydroxymethylene groups of the cage dimer and the single hydroxy group as well as the urea carbonyl group of A- 98881, respectively. In order to compare the binding possibilities to the enzyme HIV-1 protease for the cage dimer and A-98881, their interaction fields with certain probes (CH3 for alkyl, NHamide, and carbonyl, O– of COO–), representing the decisive functional groups of the active site, have been calculated using GRID and projected into the enzyme placing the structures according to the position of A-98881 in the enzyme- inhibitor complex. The strongest calculated fields of the O– probe were found near Asp 25 for both structures. Another respective conformity consists in the overlap of the fields for the NHamide probe near Ile 50 and 50 for the investigated cage dimer and A-98881.     

Structural exploration of hydroxyethylamines as HIV-1 protease inhibitors: new features identified

The current study deals with chemometric modelling strategies (Naïve Bayes classification, hologram-based quantitative structure–activity relationship (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA)) to explore the important features of hydroxylamine derivatives for exerting potent human immunodeficiency virus-1 (HIV-1) protease inhibition. Depending on the statistically validated reliable and robust quantitative structure–activity relationship (QSAR) models, important and crucial structural features have been identified that may be responsible for enhancing the activity profile of these hydroxylamine compounds. Arylsulfonamide function along with methoxy or fluoro substitution is important for enhancing activity. Bulky steric substitution at the sulfonamide nitrogen disfavours activity whereas smaller hydrophobic substitution at the same position is found to be favourable. Apart from the crucial oxazolidinone moiety, pyrrolidine, cyclic urea and methyl ester functions are also responsible for increasing the HIV-1 protease inhibitory profile. Observations derived from these modelling studies may be utilized further in designing promising HIV-1 protease inhibitors of this class.     

Structure-based virtual screening of natural products as potential stearoyl-coenzyme a desaturase 1 (SCD1) inhibitors

Stearyl coenzyme A desaturase enzyme 1 (SCD1) is a key enzyme that catalyzes the conversion of saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA) and plays a vital role in lipid metabolism of tumor cells. SCD1 is overexpressed in a variety of malignant tumors, and its related inhibitors showed significant anti-tumor activity in vitro and in vivo experiments, which is a new target for tumor therapy. The focus of this study is to identify novel SCD1 inhibitors from natural products through computer simulations. First, 176,602 compounds from natural product databases were virtually screened. By molecular dynamics (MD) simulations, the ligand-protein interactions of 5 compounds with high docking manifestation were analyzed accurately. Then, MM-GBSA and MM-PBMA methods were used to verify the results. Finally, ADMET prediction was performed for the 5 compounds. As a result, two natural products with potential inhibition towards SCD1 were identified, which had the excellent docking manifestation, binding mode within SCD1 pocket and stability during molecular dynamics simulation. This study provides a meaningful model for the development and optimization of new inhibitors and anti-tumor drugs targeting SCD1.     

Structural and electronic properties of new fullerene derivatives and their possible application as HIV-1 protease inhibitors

Density functional theory (DFT) calculations have been carried out at the hybrid Becke 3-Lee–Yang–Parr; B3LYP/3-21G** level of theory to study two series of hydroxy-chalca-acetic acid-(4-pyrrolidin-1-yl-phenyl) ester [C₆₀-C₂H₄N-(4-XCOCH₂OH)C₆H₄] and hydroxy-chalcoacetic acid-[2-(2-hydroxy-acetylchalcanyl)-4-pyrrolidin-1-yl-phenyl] ester[C₆₀-C₂H₄N-(3,4-XCOCH₂OH)C₆H₄]. The X atom is O, S or Se for the two series. The vibrational spectra, physical, chemical, thermodynamics and Quantitative Structure Activity Relationship (QSAR) properties of the studied molecules are calculated and discussed. We have evaluated these molecules as HIV-1 protease inhibitors based on the hydrogenation interaction between the hydroxymethylcarbonyl (HMC) groups and the two aspartic acid of the HIV-1 protease active site. Results show that some of the investigated fullerene-based derivatives can be considered promising as HIV-1 protease inhibitors.     

3-Nitroso-4-hydroxy-5,6-benzocoumarin as a selective reagent for the spectrophotometric determination of ruthenium(III)

The pinkish-violet complex developed on interaction of ruthenium(III) with 3-nitroso-4-hydroxy-5,6-benzocoumarin (NHBC) in the pH range 5.5-8.0 can be extracted into n-butanol. The complex has an absorption maximum at 520 nm. Maximum colour development takes place after heating for 20 min on a steam-bath and the extracted complex is stable for at least 92 hr. Beer's law is followed up to 7.4 ppm of ruthenium. The molar absorptivity is 1.04 x 10(4) 1.mole(-1).cm(-1). The composition of the complex is 1 : 2 (ruthenium: NHBC). None of the other platinum metals was found to interfere in the determination of ruthenium, even though present in large excess.     

Structure-based linker optimization of 6-(2-cyclohexyl-1-alkyl)-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with diverse structures,a series of novel S-DACO analogues of 6-(2-cyclohexyl-1-allkyl)-2-(2-oxo-2-phenyl-ethylsulfanyl)pyrimidin-4(3 H)-ones were designed,synthesized and evaluated for their antiviral activities in MT-4 cells.Most of these new compounds showed moderate to good activities against wild type HIV-1 with IC_(50) values ranging from 7.55 μmol/L to 0.018 μmol/L.Among them,compound 5 c was identified as the most promising inhibitor against HIV-1 replication with an IC_(50)=0.018 μmol/L,CC_(50)=194 μmol/L,and SI=12791,which was much more potent than the reference drugs NVP and DLV and comparable to AZT and EFV.In addition,5 c also exhibited improved activity against double mutant HIV-1 strain RES056 compared to that of the reference drugs NVP/DLV and DB02.The preliminary structure-activity relationship(SAR) and molecular modeling studies were also discussed,which provides some useful indications for guiding the further rational design of new S-DACO analogues.