In silico strategies on prion pathogenic conversion and inhibition from PrPC –PrPSc

Introduction: To date, various therapeutic strategies identified numerous anti-prion compounds and antibodies that stabilize PrP^C, block the conversion of PrP^C-PrP^Sc and increased effect on PrP^Sc clearance. However, no suitable drug has been identified clinically so far due to the poor oral absorption, low blood–brain-barrier [BBB] penetration, and high toxicity. Although some of the drugs were proven to be effective in prion-infected cell culture and whole animal models, none of them increased the rate of survival compared to placebo.

Areas covered: In this review, the authors highlight the importance of in silico approaches like molecular docking, virtual screening, pharmacophore analysis, molecular dynamics, QSAR, CoMFA and CoMSIA applied to detect molecular mechanisms of prion inhibition and conversion from PrP^C-PrP^Sc.

Expert opinion: Several in silico approaches combined with experimental studies have provided many structural and functional clues on the stability and physiological activity of prion mutants. Further, various studies of in silico and in vivo approaches were also shown to identify several new small organic anti-scrapie compounds to decrease the accumulation of PrP^res in cell culture, inhibit the aggregation of a PrP^C peptide, and possess pharmacokinetic characteristics that confirm the drug-likeness of these compounds.     

Pharmacophore-based 3D-QSAR of HIF-1 inhibitors

(Aryloxyamino)benzoic acids and nicotinic/isonicotinic acids represent an important new class of small molecules that inhibit the activation of Hypoxia-Inducible Factor (HIF)-1. In order to understand the factors affecting inhibitory potency of HIF-1 inhibitors, 3 dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed. Since no receptor structure are available, the pharmacophore-based alignment was used for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The CoMFA and CoMSIA models gave reasonable statistics (CoMFA: q² = 0.564, r²=0.945; CoMSIA: q² = 0.575, r²=0.929). Both CoMFA and CoMSIA results indicate that the steric interaction is a major factor, while CoMSIA suggests importance of hydrogen bonding. These findings about steric and H-bonding effects can be useful to design new inhibitors. Equally contributed in this work.     

Three-dimensional quantitative structure: activity relationship studies on diverse structural classes of HIV-1 integrase inhibitors using CoMFA and CoMSIA

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques, were applied to a set of 89 HIV-1 integrase (IN) inhibitors (training set=61, test set=28), belonging to 11 structurally different classes. The biological data for 3' processing mechanism were used. For CoMFA calculations, three different fitting methods for alignment process were investigated. The best CoMFA model yielded the cross-validated r(2) r(2)(cv) =0.698 and the non-cross-validated r(2) (r(2))=0.947. The derived model indicated the importance of steric (60.8%) as well as electrostatic (39.2%) contributions. For CoMSIA calculations, different combinations of the fields were tested. The best CoMSIA model gave r(2)(cv) =0.724 and r(2)=0.864. This model showed that steric (30.3%), hydrogen bond donor (43.4%) and hydrogen bond acceptor (26.3%) properties played major roles in HIV-1 IN inhibition. The mapping of hydrogen bond interaction fields with the HIV-1 IN active site gave details on hydrogen bond forming between ligands and enzyme. These obtained results agree well with the experimental observations that there should be hydrogen bond interactions between ligands and Glu152, Lys156 and Lys159 residues. The results not only lead to a better understanding of structural requirements of HIV-1 IN inhibitors but also can help in the design of new IN inhibitors.     

Cytotoxic Activity and Structure Activity Relationship of Ceramide Analogues in Caki-2 and HL-60 Cells

B13, a ceramide analogue, is a ceramidase inhibitor and induces apoptosis to give potent anticancer activity. A series of thiourea B13 analogues was evaluated for their in vitro cytotoxic activities against human renal cancer Caki-2 and leukemic cancer HL-60 in the MTT assay. Some compounds (12, 15, and 16) showed stronger cytotoxicity than B13 and C6-ceramide against both tumor cell lines, and compound (12) gave the most potent activity with IC₅₀ values of 36 and 9 µM, respectively. Molecular modeling of thiourea B13 analogues was carried out by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). We obtained highly reliable and predictive CoMSIA models with cross-validated q² values of 0.707 and 0.753 and CoMSIA contour maps to show the structural requirements for potent activity. These data suggest that the amide group of B13 could be replaced by thiourea, that the stereochemistry of 1,3-propandiol may not be essential for activity and that long alkyl chains increase cytotoxicity.     

Synthesis,Antibacterial Activities,and 3D‐QSAR of Sulfone Derivatives Containing 1, 3, 4‐Oxadiazole Moiety

A series of sulfone derivatives containing 1, 3, 4‐oxadiazole moiety were prepared and evaluated for their antibacterial activities by the turbidimeter test. Most compounds inhibited growth of Ralstonia solanacearum (R. solanacearum) from tomato and tobacco bacterial wilt with high potency, among which compounds 5a and 5b exhibited the most potent inhibition against R. solanacearum from tomato and tobacco bacterial wilts with EC₅₀ values of 19.77 and 8.29 μg/mL, respectively. Our results also demonstrated that 5a, 5b , and a number of other compounds were more potent than commercial bactericides Kocide 3000 and Thiodiazole Copper, which inhibited R. solanacearum from tomato bacterial wilt with EC₅₀ values of 93.59 and 99.80 μg/mL and tobacco bacterial wilt with EC₅₀ values of 45.91 and 216.70 μg/mL, respectively. The structure–activity relationship (SAR) of compounds was studied using three‐dimensional quantitative structure–activity relationship (3D‐QSAR) models created by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) based on compound bioactivities against tomato and tobacco bacterial wilts. The 3D‐QSAR models effectively predicted the correlation between inhibitory activity and steric–electrostatic properties of compounds.     

CoMFA, CoMSIA, and docking studies on thiolactone-class of potent anti-malarials: identification of essential structural features modulating anti-malarial activity

The integrated ligand‐ and structure‐based drug design techniques have been applied on a homogeneous dataset of thiolactone‐class of potent anti‐malarials, to explore the essential structural features for the inhibition of Plasmodium falciparum. Developed CoMFA (q² = 0.716) and CoMSIA (q² = 0.632) models well explained structure–activity variation in both the training (CoMFA R² = 0.948 & CoMSIA R² = 0.849) and test set (CoMFA R²_pred = 0.789 & CoMSIA R²_pred = 0.733) compounds. The docking and scoring of the most active compound 10 into the active site of high‐resolution (2.35 Å) structure of FabB‐TLM binary complex (PDB‐ID: 1FJ4) indicated that thiolactone core of this compound forms bifurcated H‐bonding with two catalytic residues His298 and His333, and its saturated decyl side group is stabilized by hydrophobic interactions with the residues of a small hydrophobic groove, illustrating that the active site architecture, including two catalytic histidines and a small hydrophobic groove, is vital for protein–ligand interaction. In particular, the length and flexibility of the side group attached to the position 5 of thiolactone have been observed to play a significant role in the interaction with FabB enzyme. These results present scope for rational design of thiolactone‐class of compounds that could furnish improved anti‐malarial activity.     

3D‐QSAR studies of cytotoxic heterocyclic quinones using calculated reduction potential

Most quinones with 2–4 fused aromatic rings exhibit cytostatic activity via DNA intercalation that causes enzyme blockade and reading errors during the replication process. The redox activity of quinones plays a role in the DNA cleavage mediated by oxygen or sulfur radicals. To develop novel anticancer agents based on nitrogen‐containing heterocyclic quinones, pharmacophore models of representative molecules with high activity were generated using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). A series of compounds were aligned to the selected pharmacophore model and the 3D‐quantitative structure activity relationships (QSAR) were analyzed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), resulting in q² values of 0.734 and r² of 0.951, and q² of 0.803 and r² of 0.917, respectively, in each study. In addition, the potentials for the one‐electron reduction of quinones were calculated from LUMO energies using the semi‐empirical Austin Model 1 (AM1) method. These also showed a good correlation (r² of 0.816) with the cytotoxic activities of the quinones. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.     

Pharmacophore based 3D-QSAR study of VEGFR-2 inhibitors

The growth and metastasis of solid tumors are dependent on angiogenesis. The vascular endothelial growth factor (VEGF) is of particular interest since it is essential for angiogenesis. The development of novel inhibitors of VEGF receptor type 2 (VEGFR-2) is important. Quantitative structure–activity relationship (QSAR) studies were performed to understand the structural factors affecting inhibitory potency of 4-aryl-5-cyano-2-aminopyrimidines. Pharmacophore models indicate that the importance of steric and hydrogen bond acceptor groups. The best-fitted pharmacophore-based alignment was used for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Both CoMFA (q ² = 0.62, r ² = 0.87, and r ² _predictive = 0.7) and CoMSIA (q ² = 0.54, r ² = 0.86, and r ² _predictive = 0.61) gave reasonable results. Factors such as steric bulkiness, electrostatic effect, and hydrogen bond acceptor were found to be important for the inhibitory activity. It is suggested that negatively charged, bulky H-bond accepting groups around the piperazine nitrogen would enhance inhibition against VEGFR-2.