Visualizing The Future of Molecular Graphics

Abstract

The field of computer graphics has played an important role in the advancement of structural molecular biology and in the development of structure-based drug design. This article will provide a brief background on the development of this technology, and then focus on the current trends and future directions in molecular graphics and how they will impact the practice of molecular modeling and design. Specific areas that will be covered include: 1) the development of surface and volume based representations of molecular properties and interactions; 2) new approaches to modeling flexible and multi-component structures, and 3) the impact of object-oriented graphics-based programming and the rapidly growing use of network based computing.     

Molecular heterogeneity and antiviral and interferon-inducing activities of the drug Savrats

The molecular-mass distribution of the drug Savrats has been studied by gel filtration on HW-55 f. It has been shown that the drug is heterogeneous and that the fraction with a molecular mass of 25–25 kDa exhibits a high biological activity.Mirzo Ulugbek Tashkent State University, fax (3712) 46 24 72. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 112–114, January–February, 1998.     

Molecular modeling, theoretical calculations and property evaluation of three muscarinic agonists. X-ray structures of LU 25-109 and WAL 2014

LU 25-109 (II) and WAL 2014 (talsaclidine, III) are two M1 muscarinic agonists chemically related to the natural substance arecoline (I). All these compounds have beneficial effects on memory and cognition in animals and humans, and they have been proposed in the treatment of Alzheimer's disease, but only III will likely find a place in therapy. In this work we have investigated the solid state structures of II and III, and the X-ray structures of the two molecules and of the parent compound I have been used to input a series of computational chemistry efforts.

In particular, the X-ray geometries have been manipulated to model 20 molecular structures (1–20) which have been submitted to ab initio, semiempirical quantum mechanics and molecular mechanics calculations. The conformational space accessible to the 20 structures has been assessed by means of potential energy maps. The reactivities of 1–20 have been estimated by examining at the graphics terminal the composition and the extension of the frontier orbitals (HOMOs and LUMOs) and of the molecular electrostatic potential. The information obtained has been interpreted to explain the different degrees of activity shown by I–III. Our data indicate that III has better in vivo activity for its intermediate size, less polar surface, conformational rigidity and orientation of reactive domains.     

Molecular and crystalline structure of 2-methyl-4,4-diphenyl-5-phenylazo-2-thia-3-aza-4-phosphahepta-2,4-diene-6-one-2-oxide

The molecular structure of 2-methyl-4,4-diphenyl-5-phenylazo-2-thia-3-aza-4-phosphahepta-2,4-diene-6-one-2-oxide has been determined by x-ray crystallography. The sulfur and phosphorus atoms exhibited distorted tetrahedral coordination. The P-N and P=C bond lengths are intnermediate between single and double bond lengths. Delocalization of -electron density was observed in the flattened molecular fragment Ph–N=N–C(=P)–C(=O)–CH₃.Institute of Physiologically Active Substances, Russian Academy of Sciences, 142432 Chernogolovka. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 12, pp. 2737–2741, December, 1992.     

Equilibrium Structure of Beryllium Dibromide from Combined Gas Electron Diffraction and Vibrational Spectroscopy Analysis

The molecular structure of BeBr₂ has been investigated by gas-phase electron diffraction at the temperature 800(10) K. The conventional analysis yielded the following values: r _g(Be–Br) = 1.944(6)Å, l(Be–Br) = 0.068(4)Å, r _g(Br–Br) = 3.848(8)Å, l(Br–Br) = 0.109(3)Å, k(Be–Br) = 1.1(1.1) × 10^–5 ų, (Br–Br) = 2.1(1.0) × 10^–5 ų. Three models of nuclear dynamics were used to simulate the conventional analysis values—infinitesimal vibrations and two models, which take into account the kinematic and dynamic anharmonicity of the bending vibration. All models give similar values of bond angle, amplitudes, and shrinkage, excluding the harmonic model, which yields too low value l(Br–Br). The equilibrium bond distance r _e(Be–Br) = 1.932(11) Å was estimated, taking into account the anharmonicity corrections for stretching and bending vibrations and centrifugal distortion.     

Inclusion of conserved buried water molecules in the model structure of rat submaxillary kallikrein

A new approach to the molecular modelling of homologous serine proteases isadopted, by including a set of 21 buried waters known to be preserved inenzymes sharing the primary specificity of trypsin, in the homology modellingof rat submaxillary gland kallikrein. Buried waters – water moleculessequestered from bulk solvent within a protein matrix – appear to beintegral conserved components of all serine proteases of known structure andshould be incorporated into serine protease models built on the basis ofsequence/structural homology to this family. The absence of such waters mightinduce errors in a force field simulation, favouring the formation ofnonexistent hydrogen bonds and locally inaccurate structure. The kallikreinmodel refinement has led to the conclusion that an additional buried watershould be added to the original rigid matrix of 21 conserved water molecules.The structurally preserved protein cavities of such waters validate themodelled structure.     

Molecular and crystal structures of argolide epoxide

The sesquiterpene lactone argolide has been converted into its 1(10)-epoxide. The structure of the latter has been investigated by NMR, x-ray structural analysis, and molecular mechanics.Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 60–64, January–February, 1998.     

Predicting Accurate Lead Structures for Screening Molecular Libraries: A Quantum Crystallographic Approach

Optimization of lead structures is crucial for drug discovery. However, the accuracy of such a prediction using the traditional molecular docking approach remains a major concern. Our study demonstrates that the employment of quantum crystallographic approach-counterpoise corrected kernel energy method (KEM-CP) can improve the accuracy by and large. We select human aldose reductase at 0.66 Å, cyclin dependent kinase 2 at 2.0 Å and estrogen receptor β at 2.7 Å resolutions with active site environment ranging from highly hydrophilic to moderate to highly hydrophobic and several of their known ligands. Overall, the use of KEM-CP alongside the GoldScore resulted superior prediction than the GoldScore alone. Unlike GoldScore, the KEM-CP approach is neither environment-specific nor structural resolution dependent, which highlights its versatility. Further, the ranking of the ligands based on the KEM-CP results correlated well with that of the experimental IC₅₀ values. This computationally inexpensive yet simple approach is expected to ease the process of virtual screening of potent ligands, and it would advance the drug discovery research.     

Modelling of α-lactalbumin from the known structure of hen egg white lysozyme using molecular dynamics

Summary The prediction of protein conformation by homology is being widely pursued using interactive computer graphics. However, there have been a limited number of energy minimization and/or molecular dynamics studies for such predictions. This paper reports one such study on -lactalbumin, a system that can be tested as the X-ray crystal structure has recently been determined. The differences in structure of the Ca²⁺ binding loop reported for the holo-protein (Stuart et al., Nature, 324 [1986] 84–87) and that predicted for the apoprotein could be attributed to the presence or absence of the Ca²⁺ ion.     

Thermally induced early events of ribonuclease A under reducing conditions: Evidenced by principal component analysis and two-dimensional correlation infrared spectroscopy

The thermally induced unfolding of ribonuclease A in the presence of 2-mercaptoethanol has been followed by fluorescence spectroscopy and Fourier transform infrared (FTIR) spectroscopy. Principal component analysis (PCA) in combination with two-dimensional (2D) infrared correlation spectroscopy has been employed as an attractive method for the investigation of subtle pretransitional conformational changes in the protein. Separate analyses of different stages indicated that, in stage I the change of β1(43–49) and α2(24–34) might be the main process; in stage II, β1 was further unfolded, changes of α1(3–13) and another species of β2(61–63) and β4(79–87) involved. Furthermore, quantitative analysis of the power spectra extracted from the synchronous 2D contour maps revealed that the intensity variations from pretransitional stages (below 47 °C) were 5% less than that for the main unfolding. Meanwhile, under reducing conditions the early subtle structural changes occurred in a non-cooperative manner, in contrast to what was found under non-reducing conditions.     

Ion mobility–mass spectrometry: a new paradigm for proteomics

Matrix-assisted laser desorption/ionization (MALDI) coupled with ion mobility–mass spectrometry (IM–MS) provides a rapid (μs–ms) means for the two-dimensional (2D) separation of complex biological samples (e.g., peptides, oligonucleotides, glycoconjugates, lipids, etc.), elucidation of solvent-free secondary structural elements (e.g., helices, β-hairpins, random coils, etc.), rapid identification of post-translational modifications (e.g., phosphorylation, glycosylation, etc.) or ligation of small molecules, and simultaneous and comprehensive sequencing information of biopolymers. In IM–MS, protein-identification information is complemented by structural characterization data, which is difficult to obtain using conventional proteomic techniques. New avenues for enhancing the figures of merit (e.g., sensitivity, limits of detection, dynamic range, and analyte selectivity) and optimizing IM–MS experimental parameters are described in the context of deriving new information at the forefront of proteomics research.     

Studies of electronic structures of 1,1′-disubstituted silaoxacyclohexa-3,5-dienes

Spatial and electronic structures of 1,1-disubstituted silaoxacyclohexa-3,5-dienes have been calculated using the AMPAC and HYPERCHEM 3.0 program packages. Interatomic distances, bond angles, torsion angles, atomic charges, electron densities, bond orders, parameters of localized molecular Orbitals,etc. have been determined. Based on data obtained, it has been concluded that the -R'SiO-fragment in these molecules is a saturated structural linkage, which exhibits an inductive effect on the diene system; however, the linkage does not interact with the diene system by the mesomeric (resonance) mechanism.Translated fromIzvestiya Akademii Nauk. Setiya Khimicheskaya, No. 10, pp. 1917–1920, October, 1995.     

X-Ray structural investigation of the alkaloid speciosine

The molecular and crystalline structures of a tropolone alkaloid of the colchicine series — speciosine — have been determined by x-ray structural analysis. It has been established that the presence of an orthohydroxyphenyl group does not lead to appreciable changes of the colchicine skeleton in the speciosine molecule. In the crystals, the speciosine molecules are linked into zigzag chains through O6–HO1 intermolecular H-bonds.Translated from Khimiya Prirodnykh Soedinenii, No 4, pp. 608–612, July–August, 1997.     

Porphyrin Clathrates. Crystal Structures of Two Unexpected Products Obtained by Solvothermal Reactions of Pt-tetra(4-carboxyphenyl)porphyrin with Copper Acetate

The X-ray crystal structure of IX, perchlorate salt of R-(–-2-ethyl-N-benzyl-4,7,19,13-tetraoxa-8,9-benzo-1-azacyclopentadec-8-ene has been determined. In the molecule, the protonated nitrogen atom participates in two N-HO hydrogen bonds. The unusually high proton affinity of aza crown ether leads to the formation of diastreomer instead of complex formation with chiral R-(+)-1-phenyl ethyl ammonium perchlorate and S-(–)-1-phenyl ethyl ammonium perchlorate. The complex ability of host ethers was evaluated in terms of structural modification.     

Asymmetric nitrogen

The molecular structure of 3-methyl-1-((S)-1-tosylprolyl)1,2-diazacyclohex-2-ene, the product of the reaction of 5-methyl-1,6-diazabicyclo[3.1.0]hexane with (S)-N-tosylproline chloride, has been established by X-ray structural analysis. The pyrrolidine cycle has a half-chair conformation with the pyramidal nitrogen atom; the tosyl and pseudo axial carbamoyl groups havetrans orientations. The diazacyclohexene cycle has an envelope conformation with folding along the C(7)...C(9) line. The stereochemistry of the transition state of the above-mentioned reaction is discussed.For the previous communication, see Ref. 1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 500–503, March, 1995.     

Liquid chromatography with triple-quadrupole or quadrupole-time of flight mass spectrometry for screening and confirmation of residues of pharmaceuticals in water

LC–MS–MS has been performed with triple-quadrupole (QqQ) and quadrupole-time of flight (Q-ToF) instruments and has been used for screening and confirmation of pharmaceuticals in surface, drinking, and ground water. Screening was based on monitoring of one specific MS–MS ion of the target compounds. Confirmation of the identity of the pharmaceuticals was based either on the monitoring of two specific MS–MS ions and calculation of the ratio of their intensities, or on the exact masses of MS–MS product ions obtained for a molecular ion by use of LC–Q-ToF MS. The set of pharmaceuticals included four analgesics (acetylsalicylic acid, diclofenac, ibuprofen, and paracetamol), three antibiotics (sulfamethoxazole, erythromycin, and chloramphenicol), five blood-lipid regulators and beta-blockers (fenofibrate, bezafibrate, clofibric acid, bisoprolol, and metoprolol), and the anti-epileptic drug carbamazepine. Limits of quantification ranged from 5 to 25 ng L^–1. Fifty-six samples were analysed and residues of the pharmaceuticals were detected in almost all surface and groundwater and in some drinking water samples. The identity of the compounds could be confirmed by use of both QqQ- and Q-ToF-based LC–MS–MS. However, the latter technique has the distinct advantage that a large number of pharmaceuticals can be screened and confirmed at low concentrations (1–100 ng L^–1) in one run.     

Natural product drug discovery in the artificial intelligence era

Natural products (NPs) are primarily recognized as privileged structures to interact with protein drug targets. Their unique characteristics and structural diversity continue to marvel scientists for developing NP-inspired medicines, even though the pharmaceutical industry has largely given up. High-performance computer hardware, extensive storage, accessible software and affordable online education have democratized the use of artificial intelligence (AI) in many sectors and research areas. The last decades have introduced natural language processing and machine learning algorithms, two subfields of AI, to tackle NP drug discovery challenges and open up opportunities. In this article, we review and discuss the rational applications of AI approaches developed to assist in discovering bioactive NPs and capturing the molecular “patterns” of these privileged structures for combinatorial design or target selectivity.

Natural products (NPs) are primarily recognized as privileged structures to interact with protein drug targets.     

Analysis of the electron density redistribution in the course of nucleophilic addition reactions of H− and F− to acetylene and methylacetylene molecules according toab initio calculations

Energy characteristics and peculiarities of variation of structural parameters along the minimum energy pathways (MEP) calculated earlier of six reactions of nucleophilic addition of H^– and F^– to acetylene and methylacetylene have been analyzed. The electronic mechanism of the reactions, the character of the electron density redistribution, and its relation with the changes in structural parameters have been discussed. It has been found for all six reactions that the structural reorganization of an alkyne + Nu system is completed before the barriers. However, the increase in the alkyne multiple bond length and changes in electronic characteristics for the reactions with F^– (endothermic reactions) take place before the barrier (late transition state) and for the reaction with H^– (exothermic reactions), after the barrier (early transition state).Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2373–2377, December, 1995.     

Ligand docking and binding site analysis with PyMOL and Autodock/Vina

Docking of small molecule compounds into the binding site of a receptor and estimating the binding affinity of the complex is an important part of the structure-based drug design process. For a thorough understanding of the structural principles that determine the strength of a protein/ligand complex both, an accurate and fast docking protocol and the ability to visualize binding geometries and interactions are mandatory. Here we present an interface between the popular molecular graphics system PyMOL and the molecular docking suites Autodock and Vina and demonstrate how the combination of docking and visualization can aid structure-based drug design efforts.     

Crystal structure of the molecular complex (1∶1) of (o-hydroxyphenylaminomethyl)chloromethylphosphinic acid with dioxane

The crystal structure of the molecular complex (11) of (o-hydroxyphenylaminomethyl)chloromethylphosphinic acid with dioxane has been studied by x-ray structural analysis and it has been established that the acid exists in the zwitterion form.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 572–574, March, 1990.