Structure-based 3D-QSAR studies on thiazoles as 5-HT<Subscript>3</Subscript> receptor antagonists

Structure-based 3D-QSAR studies were performed on 20 thiazoles against their binding affinities to the 5-HT₃ receptor with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The thiazoles were initially docked into the binding pocket of a human 5-HT_3A receptor homology model, constructed on the basis of the crystal structure of the snail acetylcholine binding protein (AChBP), using the GOLD program. The docked conformations were then extracted and used to build the 3D-QSAR models, with cross-validated values 0.785 and 0.744 for CoMFA and CoMSIA, respectively. An additional five molecules were used to validate the models further, giving satisfactory predictive values of 0.582 and 0.804 for CoMFA and CoMSIA, respectively. The results would be helpful for the discovery of new potent and selective 5-HT₃ receptor antagonists.      

Computational studies of the binding site of α<Subscript>1A</Subscript>-adrenoceptor antagonists

Aimed at achieving a good understanding of the 3-dimensional structures of human α_1A-adrenoceptor (α_1A-AR), we have successfully developed its homology model based on the crystal structure of β₂-AR. Subsequent structural refinements were performed to mimic the receptor’s natural membrane environment by using molecular mechanics (MM) and molecular dynamics (MD) simulations in the GBSW implicit membrane model. Through molecular docking and further simulations, possible binding modes of subtype-selective α_1A-AR antagonists, Silodosin, RWJ-69736 and (+)SNAP-7915, were examined. Results of the modeling and docking studies are qualitatively consistent with available experimental data from mutagenesis studies. The homology model built should be very useful for designing more potent subtype-selective α_1A-AR antagonists and for guiding further mutagenesis studies. Figure The superposition of β₂-AR crystal structure (gold ribbons) and α_1A-AR homology model (blue ribbons)     

Model of the whole rat AT1 receptor and the ligand-binding site

We present a three-dimensional model of the rat type 1 receptor (AT₁) for the hormone angiotensin II (Ang II). Ang II and the AT₁ receptor play a critical role in the cell-signaling process responsible for the actions of renin–angiotensin system in the regulation of blood pressure, water-electrolyte homeostasis and cell growth. Development of improved therapeutics would be significantly enhanced with the availability of a 3D-structure model for the AT₁ receptor and of the binding site for agonists and antagonists. This model was constructed using a combination of computation and homology-modeling techniques starting with the experimentally determined three-dimensional structure of bovine rhodopsin (PDB#1F88) as a template. All 359 residues and two disulfide bonds in the rat AT₁ receptor have been accounted for in this model. Ramachandran-map analysis and a 1 nanosecond molecular dynamics simulation of the solvated receptor with and without the bound ligand, Ang II, lend credence to the validity of the model. Docking calculations were performed with the agonist, Ang II and the antihypertensive antagonist, losartan.      

Adsorption and phase transitions in adsorbed systems: structural properties of CCl<Subscript>4</Subscript> layers adsorbed on a graphite surface

We present the results of simulations of a CCl₄ monolayer adsorbed on a graphite surface. The CCl₄ molecule was represented either by a shapeless superatom or by its atomic sites. The simulations were carried out over a large range of temperatures, from 20 K up to 340 K. We address the following problems: (1) the influence of molecular shape on the structure and stability of phases (particularly at low temperatures), and (2) the influence of the graphite corrugation on layer stability and mechanism of phase transitions. In particular, we discuss the possibility and conditions of the appearance of hexatic phase in the system. Figure Temperature dependence of Φ6 order parameter for CCl₄ monolayer adsorbed onsmooth and corrugated surfaces, in the spherical Lennard Jones (LJ) approximation.For comparison, the order parameter calculated for MacDonald’s five-site potential is also presented     

Docking studies suggest ligand-specific δ-opioid receptor conformations

An automated docking procedure was used to study binding of a series of δ-selective ligands to three models of the δ-opioid receptor. These models are thought to represent the three ligand-specific receptor conformations. Docking results are in agreement with point mutation studies and suggest that different ligands—agonists and antagonists—may bind to the same binding site under different receptor conformations. Docking to different receptor models (conformations) also suggests that by changing to a receptor-specific conformation, the receptor may open or close different binding sites to other ligands. Figure  Ligands 5 (green) and 6 (orange) in bindingpocket BP1 of the R1 δ-opioid receptor model     

The platinum-olefin binding energy in series of (PH<Subscript>3</Subscript>)<Subscript>2</Subscript>Pt(olefin) complexes - a theoretical study

Theoretical investigation of Pt(0)-olefin organometallic complexes containing tertiary phosphine ligands was focused on the strength of platinum-olefin electronic interaction. DFT theoretical study of electronic effects in a substantial number of ethylene derivatives was evaluated in terms of the Pt-olefin binding energy using MP2 correlation theory. Organometallics bearing coordinated olefins with general formula (R¹R²C = CR³R⁴)Pt(PH₃)₂ [R = various substituents] had been selected, including olefins containing both electron-donor substituents as well as electron-withdrawing groups. The stability of the corresponding complexes increases with a strengthening electron-withdrawal ability of the olefin substituents. Figure Representation of (CH₂ = CHR)Pt(PPh₃)₂ and the stability chart     

Theoretical study of the novel sandwich compound [Au<Subscript>3</Subscript>Cl<Subscript>3</Subscript>Tr<Subscript>2</Subscript>]<Superscript>2+</Superscript>

A theoretical study of a sandwich compound with a metal monolayer sheet between two aromatic ligands is presented. A full geometry optimization of the [Au₃Cl₃Tr₂]²⁺ (1) compound, which is a triangular gold(I) monolayer sheet capped by chlorines and bounded to two cycloheptatrienyl (Tr) ligands was carried out using perturbation theory at the MP2 computational level and DFT. Compound (1) is in agreement with the 18–electron rule, the bonding nature in the complex may be interpreted from the donation interaction coming from the Tr rings to the Au array, and from the back-donation from the latter to the former. NICS calculations show a strong aromatic character in the gold monolayer sheet and Tr ligands; calculations done with HOMA, also report the same aromatic behavior on the cycloheptatrienyl fragments giving us an insight on the stability of (1). The Au –Au bond lengths indicate that an intramolecular aurophilic interaction among the Au(I) cations plays an important role in the bonding of the central metal sheet. Figure (a) Ground state geometry of complex 1; (b) Top view of compound 1 and Wiberg bond orders computed with the MP2/B1 computational method; (c) Lateral view of compound 1 and NICS values calculated with the MP2/B1 method; the values in parenthesis were obtained at the VWN/TZP level     

Ligation of Aza bases to the AgF<Subscript>2</Subscript> molecule: a theoretical study

We have analyzed the electronic structure and chemical bonding for molecular adducts of the Ag(II)F₂ molecule with various aza Lewis bases including ammonia, nitriles, secondary amines, and their derivatives exhibiting various degrees of fluorination. Density functional theory calculations indicate that a progressive shift occurs of the spin density from the Ag center towards the coordinating nitrogen atoms of aza ligands, as the ligation energy increases. Chemistry of Ag(II) might be extended with little effort beyond the known aza connections, to include nitriles, perfluorinated nitriles and perfluorinated amines. Figure Properties of a variety of novel adducts of the AgF₂ molecule with two aza bases (L), possible precursors of the AgF₂L₂ extended solids, were assessed by the DFT calculations Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. This work is dedicated to memory of Wojciech Ochmański, unforgettable person, good-hearted man, whose craftsmanship in work was second-to-none.     

Alpha particle chemistry. On the formation of stable complexes between He2+ and other simple species: implications for atmospheric and interstellar chemistry

The possibility that stable complexes may be formed between alpha particles (He²⁺) and small molecules is investigated using QCISD quantum mechanical calculations. Implications for their presence in the terrestrial atmosphere and/or in interstellar space are discussed. Figure Optimized structure of a stable H₂OHe²⁺ complex     

Exploring the binding pocket for pyridopyrimidine ligands at the CCK1 receptor by molecular docking

Pyridopyrimidine-based analogues are among the most highly potent and selective antagonists of cholecystokinin receptor subtype-1 (CCK1R) described to date. To better understand the structural and chemical features responsible for the recognition mechanism, and to explore the binding pocket of these compounds, we performed automated molecular docking using GOLD2.2 software on some derivatives with structural diversity, and propose a putative binding conformation for each compound. The docking protocol was guided by the key role of the Asn333 residue, as revealed by site directed mutagenesis studies. The results suggest two putative binding modes located in the same pocket. Both are characterized by interaction with the main residues revealed by experiment, Asn333 and Arg336, and differ in the spatial position of the Boc-Trp moiety of these compounds. Hydrophobic contacts with residues Thr117, Phe107, Ile352 and Ile329 are also in agreement with experimental data. Despite the poor correlation obtained between the estimated binding energies and the experimental activity, the proposed models allow us to suggest a plausible explanation of the observed binding data in accordance with chemical characteristics of the compounds, and also to explain the observed diastereoselectivity of this family of antagonists towards CCK1R. The most reasonable selected binding conformations could be the starting point for future studies. Figure Superimposition of the two putative binding conformations revealed by molecular docking for pyridopyrimidine-based CCK1 antagonists     

Molecular electrostatic potentials in aromatic substituted 4-hydroxyquino-2-lones: Glycine/NMDA receptor antagonists

Hydroxyquinolone derivatives have proven to be useful for inhibition at the glycine binding site of N-methyl-D-aspartate (NMDA) receptor. In this work the electronic structure, molecular electrostatic potential (MESP) and vibrational characteristics of a set of C₃ substituted 4-hydroxyquino-2-lone (HQ) derivatives, which act as Glycine/NMDA receptor antagonists, have been investigated using the density functional calculations. In the optimized structures a substituent at the C₃ site of HQ tends to adopt a helical structure. MESP investigations reveal that the ligands showing better inhibition activity should possess electron-rich regions extending over the substituent and carbonyl group of HQ. A correlation of inhibitory activity to the molecular electrostatic potential topography at the carbonyl oxygen as well as to the molecular electron density topography turns out to be a significant output of the investigation. Figure Quantam chemical approach has been employed to understand the reactivity of a set of hydroxyquinolone derivatives known for their inhibition activity towards Glycine/NMDA receptor. Molecular electrostatic potential topography has been used as a tool to understand the reactivity pattern     

ParaFrag—an approach for surface-based similarity comparison of molecular fragments

A frequent task in computer-aided drug design is to identify novel chemotypes similar in activity but structurally different to a given reference structure. Here we report the development of a novel method for atom-independent similarity comparison of molecular fragments (substructures of drug-like molecules). The fragments are characterized by their local surface properties coded in the form of 3D pharmacophores. As surface properties, we used the electrostatic potential (MEP), the local ionization energy (IE_L), local electron affinity (EA_L) and local polarizability (POL) calculated on isodensity surfaces. A molecular fragment can then be represented by a minimal set of extremes for each surface property. We defined a tolerance sphere for each of these extremes, thus allowing us to assess the similarity of fragments in an analogous manner to classical pharmacophore comparison. As a first application of this method we focused on comparing rigid fragments suitable for scaffold hopping. A retrospective analysis of successful scaffold hopping reported for Factor Xa inhibitors [Wood MR et al (2006) J Med Chem 49:1231] showed that our method performs well where atom-based similarity metrics fail. Figure Encoding surface hotspots as a ParaFrag pharmacophore     

Pharmacophore mapping of a series of pyrrolopyrimidines,indolopyrimidines and their congeners as multidrug-resistance-associated protein (MRP1) modulators

Pharmacophore mapping studies were undertaken for a series of molecules belonging to pyrrolopyrimidines, indolopyrimidines and their congeners as multidrug resistance-associated protein (MRP1) modulators. A five-point pharmacophore with two hydrogen bond acceptors (A), one lipophilic/hydrophobic group (H), one positive ionic feature (P) and one aromatic ring (R) as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r ² = 0.799 for training set molecules. The model generated showed excellent predictive power, with a correlation coefficient Q ² = 0.679 for an external test set of 20 molecules. The pharmacophore was further validated using four structurally diverse compounds with MRP1 modulatory activity. These compounds mapped well onto four of the five features of the pharmacophore. The pharmacophore proposed here was then utilised for the successful retrieval of active molecules with diverse chemotypes from database search. The geometry and features of pharmacophore are expected to be useful for the design of selective MRP1 inhibitors. Figure Alignment of multidrug resistance-associated protein (MRP1) inhibitors with the developed pharmacophore. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Molecular modeling and biophysical analysis of the c-MYC NHE-III<Subscript>1</Subscript> silencer element

G-Quadruplex and i-Motif-forming sequences in the promoter regions of several oncogenes show promise as targets for the regulation of oncogenes. In this study, molecular models were created for the c-MYC NHE-III₁ (nuclease hypersensitivity element III₁) from two 39-base complementary sequences. The NHE modeled here consists of single folded conformers of the polypurine intramolecular G-Quadruplex and the polypyrimidine intramolecular i-Motif structures, flanked by short duplex DNA sequences. The G-Quadruplex was based on published NMR structural data for the c-MYC 1:2:1 loop isomer. The i-Motif structure is theoretical (with five cytosine–cytosine pairs), where the central intercalated cytosine core interactions are based on NMR structural data obtained for a tetramolecular [d(A₂C₄)₄] model i-Motif. The loop structures are in silico predictions of the c-MYC i-motif loops. The porphyrin meso-tetra(N-methyl-4-pyridyl)porphine (TMPyP4), as well as the ortho and meta analogs TMPyP2 and TMPyP3, were docked to six different locations in the complete c-MYC NHE. Comparisons are made for drug binding to the NHE and the isolated G-Quadruplex and i-Motif structures. NHE models both with and without bound cationic porphyrin were simulated for 100 ps using molecular dynamics techniques, and the non-bonded interaction energies between the DNA and porphyrins calculated for all of the docking interactions. Figure Molecular models of the average structure of the final 20 ps of the molecular dynamics simulation of the c-MYC NHE-III₁ (nuclease hypersensitivity element III₁) “silencer” element. The G-Quadruplex structure is at the top-center, and the i-Motif is at the bottom-center of each picture. a “Rotation #1” of the G-Quadruplex, with the T15 loop at the top and rear and the G19/A20 loop at the top and front of the picture. b “Rotation #2” of the G-Quadruplex, with the T15 loop at the top and front of the image, and the G19/A20 loop at the front and adjacent to the G-Quadruplex/i-Motif interface     

An ab initio quantum mechanical drug designing procedure: application to the design of balanced dual ACE/NEP inhibitors

This article describes in a sequential fashion how ab initio quantum mechanical methods can be applied to study the pharmacophoric features of drugs. It also describes how accurate drug–receptor interaction calculations can guide the careful design of balanced dual inhibitors, which form an important class of second generation drugs. As an example, the authors have chosen balanced inhibitors of angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) as modern antihypertensive drugs. A unified, accurate, in silico design approach is presented, encompassing all steps from pharmacophore derivation to complete understanding of mechanistic aspects leading to drug design.      

Conformational stability and three-dimensional model of the δ-opioid pharmacophore for the extended antiparallel dimer structure of Met-enkephalin in water

The conformational stability of the extended antiparallel dimer structure of Met-enkephalin in water was analyzed by examining the hydration structure of enkephalin using molecular dynamics simulations. The result shows that, despite of the hydrophicility of the terminal atoms in the pentapeptide, the main contributor for the stability of the dimer in water is the four intermolecular hydrogen bonds between the Gly² and Phe⁴ groups. The three-dimensional model of the δ-opioid pharmacophore for this dimer structure was also established. Such a model was demonstrated to match the δ-opioid pharmacophore query derived from the non-peptides SIOM, TAN-67, and OMI perfectly. This result thus strongly supports the assumption that the dimer structure of Met-enkephalin is a possible δ-receptor binding conformation. Figure Schematic model of the extended antiparallel dimer structure of Met-enkephalin     

A theoretical investigation of cytotoxic activity of celastroid triterpenoids

Quantum chemical calculations at the B3LYP/6-31G* level of theory have been carried out on 20 celastroid triterpenoids to obtain a set of molecular electronic properties and to correlate these with cytotoxic activities. The cytotoxic activities of these compounds can be roughly correlated with electronic effects related to nucleophilic addition to C(6) of the compounds: The energies of the frontier molecular orbitals (E _HOMO and E _LUMO), the HOMO-LUMO energy gap, the dipole moment, the charge on C(6), and the electrophilicity on C(6). Figure LUMO of Pristimerin.     

3D pharmacophore models for thromboxane A2 receptor antagonists

Thromboxane A₂ (TXA₂) is an endogenous arachidonic acid derivative closely correlated to thrombosis and other cardiovascular diseases. The action of TXA₂ can be effectively inhibited with TXA₂ receptor antagonists (TXRAs). Previous studies have attempted to describe the interactions between the TXA₂ receptor and its ligands, but their conclusions are still controversial. In this study, ligand-based computational drug design is used as a new and effective way to investigate the structure-activity relationship of TXRAs. Three-dimensional pharmacophore models of TXRAs were built with HypoGenRefine and HipHop modules in CATALYST software. The optimal HypoGenRefine model was developed on the basis of 25 TXRAs. It consists of two hydrophobic groups, one aromatic ring, one hydrogen-bond acceptor and four excluded volumes. The optimal HipHop model contains two hydrophobic groups and two hydrogen-bond acceptors. These models describe the key structure-activity relationship of TXRAs, can predict their activities, and can thus be used to design novel antagonists. Figure Optimal three-dimensional pharmacophore models of TXA₂ receptor antagonists (TXRAs) built with HypoGenRefine (a) and HipHop (b) modules. a Hypo-1 model mapped with compounds 11 (purple), and 20 (green). b Hypo-2 model mapped with compounds 31 (green) and 64 (yellow). Spheres: Green Hydrogen bond acceptors (HBA), cyanhydrophobic (H), orange aromatic rings (RA), black excluded volumes (EV) Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A computational approach to the synthesis of 1,3,5-thiadiazinane-2-thiones in aqueous medium: theoretical evidence for water-promoted heterocyclization

Based on experimental evidence and DFT studies, a probable cyclization route to 1,3,5-thiadiazinanes-2-thiones in aqueous medium is proposed. Experimental facts suggest the formation of a {[hydroxymethyl (substituted) carbamothioyl] sulfanyl}methanol intermediate via reaction of dithiocarbamate (DTC) and formaldehyde. Nucleophilic addition of glycine to this intermediate generates an adduct that undergoes intramolecular heterocyclization via an S_N2 reaction. Computational calculations predict an active role of water in the reaction mechanism that promotes intramolecular cyclization. Figure Energy profile of the proposed reaction mechanism for the synthesis of thiadiazinane-2-thione ring 11 in aqueous medium from a (hydroxymethylcarbamothioyl)sulfanylmethanol intermediate, 9     

Hydroxy-1,2,5-oxadiazolyl moiety as bioisoster of the carboxy function. A computational study on γ-aminobutyric acid (GABA) related compounds

Recently, our research group has proposed the hydroxyfurazanyl (4-hydroxy-1,2,5-oxadiazole-3-yl) moiety as a new non-classical isoster of the carboxy function in the design of γ-aminobutyric acid (GABA) analogues. Some compounds showed significant activity at the GABA_A receptor, representing the only examples of pentatomic heterocycles bearing an ω-aminoalkyl flexible side chain in the position vicinal to the hydroxy group displaying agonist activity at this receptor subtype. In this work, an ab initio analysis of the structural and electronic features of furazan-3-ol is presented, in order to provide a theoretical basis to the claimed bioisosterism with the carboxy function. An ab initio conformational study with the C-PCM implicit solvent model was carried out to elucidate the reasons of the peculiar behaviour of the furazan models. Alongside, another conformational search through molecular dynamics in explicit solvent was accomplished, in order to validate the first method. The electronic features of the 4-hydroxy-1,2,5-oxadiazole-3-yl substructure seem to account for a marked stabilising effect of the putative bioactive conformation at the GABA_A receptor subtype. The 1,2,5-thiadiazole analogue, which shares the same conformational preference of its oxygenated counterpart, was identified as a potential candidate for synthesis and pharmacological testing. Figure 4-(ω-aminoalkyl)-1,2,5-oxadiazole-3-ol analogues of GABA Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.