Adaptable Small Ligand of CYP1 Enzymes for Use in Understanding the Structural Features Determining Isoform Selectivity.

Although several families of compounds have been identified as scaffolds for inhibitors of the CYP1 family, the isoform selectivity determining structural features has not been fully clarified at the molecular interaction level. We studied the CYP1 isoform selectivity for stilbenoid inhibitors using integrated induced fit docking and molecular dynamics simulations. The hydrophobic interactions with the specific phenylalanine residues in the F helix are correlated with inhibitory potency in the CYP1 family.

Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein.

ATP binding cassette (ABC) transporters of the exporter class harness the energy of ATP hydrolysis in the nucleotide-binding domains (NBDs) to power the energetically uphill efflux of substrates by a dedicated transmembrane domain (TMD). Although numerous investigations have described the mechanism of ATP hydrolysis and defined the architecture of ABC exporters, a detailed structural dynamic understanding of the transduction of ATP energy to the work of substrate translocation remains elusive. Here we used double electron-electron resonance and molecular dynamics simulations to describe the ATP- and substrate-coupled conformational cycle of the mouse ABC efflux transporter P-glycoprotein (Pgp; also known as ABCB1), which has a central role in the clearance of xenobiotics and in cancer resistance to chemotherapy.

Mass spectrometry-based cross-linking study shows that the Psb28 protein binds to cytochrome in Photosystem II.

Photosystem II (PSII), a large pigment protein complex, undergoes rapid turnover under natural conditions. During assembly of PSII, oxidative damage to vulnerable assembly intermediate complexes must be prevented. Psb28, the only cytoplasmic extrinsic protein in PSII, protects the RC47 assembly intermediate of PSII and assists its efficient conversion into functional PSII.

QSAR modeling to design selective histone deacetylase 8 (HDAC8) inhibitors.

HDAC8 inhibitors have become an attractive treatment for cancer. This study aimed to facilitate the identification of potential chemical scaffolds for the selective inhibition of histone deacetylase 8 (HDAC8) using in silico approaches. Non-linear QSAR classification and regression models of HDAC8 inhibitors were developed with support vector machine.

Binding Site Recognition and Docking Dynamics of a Single Electron Transport Protein: Cytochrome c2.

Small diffusible redox proteins facilitate electron transfer in respiration and photosynthesis by alternately binding to their redox partners and integral membrane proteins and exchanging electrons. Diffusive search, recognition, binding, and unbinding of these proteins often amount to kinetic bottlenecks in cellular energy conversion, but despite the availability of structures and intense study, the physical mechanisms controlling redox partner interactions remain largely unknown. The present molecular dynamics study provides an all-atom description of the cytochrome c2-docked bc1 complex in Rhodobacter sphaeroides in terms of an ensemble of favorable docking conformations and reveals an intricate series of conformational changes that allow cytochrome c2 to recognize the bc1 complex and bind or unbind in a redox state-dependent manner.

The cellular membrane as a mediator for small molecule interaction with membrane proteins.

The cellular membrane constitutes the first element that encounters a wide variety of molecular species to which a cell might be exposed. Hosting a large number of structurally and functionally diverse proteins associated with this key metabolic compartment, the membrane not only directly controls the traffic of various molecules in and out of the cell, it also participates in such diverse and important processes as signal transduction and chemical processing of incoming molecular species. In this article, we present a number of cases where details of interaction of small molecular species such as drugs with the membrane, which are often experimentally inaccessible, have been studied using advanced molecular simulation techniques.

New insights in the activation of human cholesterol esterase to design potent anti-cholesterol drugs.

Primary hypercholesterolemia is the root cause for major health issues like coronary heart disease and atherosclerosis. Regulating plasma cholesterol level, which is the product of biosynthesis as well as dietary intake, has become one of the major therapeutic strategies to effectively control these diseases. Human cholesterol esterase (hCEase) is an interesting target involved in the regulation of plasma cholesterol level and thus inhibition of this enzyme is highly effective in the treatment of hypercholesterolemia.

Multi-conformation dynamic pharmacophore modeling of the peroxisome proliferator-activated receptor γ for the discovery of novel agonists.

Activation of the peroxisome proliferator-activated receptor γ (PPARγ) is important for the treatment of type 2 diabetes and obesity through the regulation of glucose metabolism and fatty acid accumulation. Hence, the discovery of novel PPARγ agonists is necessary to overcome these diseases. In this study, a newly developed approach, multi-conformation dynamic pharmacophore modeling (MCDPM), was used for screening candidate compounds that can properly bind PPARγ.

Molecular dynamics simulations of sonic hedgehog-receptor and inhibitor complexes and their applications for potential anticancer agent discovery.

The sonic hedgehog (Shh) signaling pathway is necessary for a variety of development and differentiation during embryogenesis as well as maintenance and renascence of diverse adult tissues. However, an abnormal activation of the signaling pathway is related to various cancers. In this pathway, the Shh signaling transduction is facilitated by binding of Shh to its receptor protein, Ptch.

Development of predictive quantitative structure-activity relationship model and its application in the discovery of human leukotriene A4 hydrolase inhibitors.

Background: Human LTA4H catalyzes the conversion of LTA4 to LTB4 and plays a key role in innate immune responses. Inhibition of this enzyme can be a valid method in the treatment of inflammatory response exhibited through LTB4.

Results & Discussion: The quantitative structure-activity relationship (QSAR) models were developed using genetic function approximation and validated.

Molecular modeling study on tunnel behavior in different histone deacetylase isoforms.

Histone deacetylases (HDACs) have emerged as effective therapeutic targets in the treatment of various diseases including cancers as these enzymes directly involved in the epigenetic regulation of genes. However the development of isoform-selective HDAC inhibitors has been a challenge till date since all HDAC enzymes possess conserved tunnel-like active site. In this study, using molecular dynamics simulation we have analyzed the behavior of tunnels present in HDAC8, 10, and 11 enzymes of class I, II, and IV, respectively.

Comparative molecular modeling study of Arabidopsis NADPH-dependent thioredoxin reductase and its hybrid protein.

2-Cys peroxiredoxins (Prxs) play important roles in the protection of chloroplast proteins from oxidative damage. Arabidopsis NADPH-dependent thioredoxin reductase isotype C (AtNTRC) was identified as efficient electron donor for chloroplastic 2-Cys Prx-A. There are three isotypes (A, B, and C) of thioredoxin reductase (TrxR) in Arabidopsis.

Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations.

Human leukotriene A4 hydrolase (hLTA4H), which is the final and rate-limiting enzyme of arachidonic acid pathway, converts the unstable epoxide LTA4 to a proinflammatory lipid mediator LTB4 through its hydrolase function. The LTA4H is a bi-functional enzyme that also exhibits aminopeptidase activity with a preference over arginyl tripeptides. Various mutations including E271Q, R563A, and K565A have completely or partially abolished both the functions of this enzyme.

Computational studies of novel chymase inhibitors against cardiovascular and allergic diseases: mechanism and inhibition.

To provide a new idea for drug design, a computational investigation is performed on chymase and its novel 1,4-diazepane-2,5-diones inhibitors that explores the crucial molecular features contributing to binding specificity. Molecular docking studies of inhibitors within the active site of chymase were carried out to rationalize the inhibitory properties of these compounds and understand their inhibition mechanism. The density functional theory method was used to optimize molecular structures with the subsequent analysis of highest occupied molecular orbital, lowest unoccupied molecular orbital, and molecular electrostatic potential maps, which revealed that negative potentials near 1,4-diazepane-2,5-diones ring are essential for effective binding of inhibitors at active site of enzyme.

Molecular docking and dynamics simulation, receptor-based hypothesis: application to identify novel sirtuin 2 inhibitors.

Sirtuin, NAD(+)-dependent histone deacetylase enzyme, emerged as a potential therapeutic target, and modulations by small molecules could be effective drugs for various diseases. Owing to the absence of complex structure of sirtuin 2 (SIRT2), sirtinol was docked in the NAD(+) binding site and subjected to 5-nseconds molecular dynamics (MD) simulation. LigandScout was used to develop hypotheses based on 3-representative SIRT2 complex structures from MD.

Molecular dynamics simulation study and hybrid pharmacophore model development in human LTA4H inhibitor design.

Human leukotriene A4 hydrolase (hLTA4H) is a bi-functional enzyme catalyzes the hydrolase and aminopeptidase functions upon the fatty acid and peptide substrates, respectively, utilizing the same but overlapping binding site. Particularly the hydrolase function of this enzyme catalyzes the rate-limiting step of the leukotriene (LT) cascade that converts the LTA4 to LTB4. This product is a potent pro-inflammatory activator of inflammatory responses and thus blocking this conversion provides a valuable means to design anti-inflammatory agents.

Construction and characterization of chimeric cellulases with enhanced catalytic activity towards insoluble cellulosic substrates.

The chimeric proteins viz. CBM3-Cel9A, CBM4-Cel9A and CBM30-Cel9A, are constructed by fusion of family 3, 4, and 30 cellulose binding modules (CBMs) to N-terminus of family 9 endoglucanase (Cel9A) from Alicyclobacillus acidocaldrious. The chimeric enzymes were successfully expressed in Escherichia coli and purified to homogeneity.

Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors.

Background: Renin has become an attractive target in controlling hypertension because of the high specificity towards its only substrate, angiotensinogen. The conversion of angiotensinogen to angiotensin I is the first and rate-limiting step of renin-angiotensin system and thus designing inhibitors to block this step is focused in this study.

Methods: Ligand-based quantitative pharmacophore modeling methodology was used in identifying the important molecular chemical features present in the set of already known active compounds and the missing features from the set of inactive compounds.

Potential human cholesterol esterase inhibitor design: benefits from the molecular dynamics simulations and pharmacophore modeling studies.

Human pancreatic cholesterol esterase (hCEase) is one of the lipases found to involve in the digestion of large and broad spectrum of substrates including triglycerides, phospholipids, cholesteryl esters, etc. The presence of bile salts is found to be very important for the activation of hCEase. Molecular dynamic simulations were performed for the apoform and bile salt complexed form of hCEase using the co-ordinates of two bile salts from bovine CEase.

Dynamic structure-based pharmacophore model development: a new and effective addition in the histone deacetylase 8 (HDAC8) inhibitor discovery.

Histone deacetylase 8 (HDAC8) is an enzyme involved in deacetylating the amino groups of terminal lysine residues, thereby repressing the transcription of various genes including tumor suppressor gene. The over expression of HDAC8 was observed in many cancers and thus inhibition of this enzyme has emerged as an efficient cancer therapeutic strategy. In an effort to facilitate the future discovery of HDAC8 inhibitors, we developed two pharmacophore models containing six and five pharmacophoric features, respectively, using the representative structures from two molecular dynamic (MD) simulations performed in Gromacs 4.

3D QSAR pharmacophore modeling, in silico screening, and density functional theory (DFT) approaches for identification of human chymase inhibitors.

Human chymase is a very important target for the treatment of cardiovascular diseases. Using a series of theoretical methods like pharmacophore modeling, database screening, molecular docking and Density Functional Theory (DFT) calculations, an investigation for identification of novel chymase inhibitors, and to specify the key factors crucial for the binding and interaction between chymase and inhibitors is performed. A highly correlating (r = 0.

Ligand-based virtual screening and molecular docking studies to identify the critical chemical features of potent cathepsin D inhibitors.

Cathepsin D is a major component of lysosomes and plays a major role in catabolism and degenerative diseases. The quantitative structure-activity relationship study was used to explore the critical chemical features of cathepsin D inhibitors. Top 10 hypotheses were built based on 36 known cathepsin D inhibitors using HypoGen/Discovery Studio v2.

Pharmacophore modeling, molecular docking, and molecular dynamics simulation approaches for identifying new lead compounds for inhibiting aldose reductase 2.

Aldose reductase 2 (ALR2), which catalyzes the reduction of glucose to sorbitol using NADP as a cofactor, has been implicated in the etiology of secondary complications of diabetes. A pharmacophore model, Hypo1, was built based on 26 compounds with known ALR2-inhibiting activity values. Hypo1 contains important chemical features required for an ALR2 inhibitor, and demonstrates good predictive ability by having a high correlation coefficient (0.

Molecular dynamics simulation study explaining inhibitor selectivity in different class of histone deacetylases.

Histone deacetylases (HDACs) are key regulators of gene expression and thereby compelling targets in the treatment of various cancers. Class- and isoform-selective HDAC inhibitors targeting the particular isoform to treat cancers without affecting the normal expression of other isoforms are highly desirable. Molecular dynamics simulations were performed with the set of selective inhibitors and HDAC isoforms of three different classes.

Discovery and evaluation of potential sonic hedgehog signaling pathway inhibitors using pharmacophore modeling and molecular dynamics simulations.

Sonic hedgehog (Shh) plays an important role in the activation of Shh signaling pathway that regulates preservation and rebirth of adult tissues. An abnormal activation of this pathway has been identified in hyperplasia and various tumorigenesis. Hence the inhibition of this pathway using a Shh inhibitor might be an efficient way to treat a wide range of malignancies.