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G R Desiraju

Publications and source records attributed to G R Desiraju.

15 recordsLinked to original sources
PubMed2005

3D-QSAR studies on antitubercular thymidine monophosphate kinase inhibitors based on different alignment methods.

Three dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out on deoxythymidine monophosphate (dTMP) derivatives inhibiting thymidine monophosphate kinase (TMPK) in Mycobacterium tuberculosis. Molecular field analysis (MFA) models with three different alignment techniques, namely, least squares, pharmacophore based and receptor based methods were developed. Receptor based MFA model showed better results when compared with least squares and pharmacophore based models. The results help us to understand the nature of substituents required for activity and thereby provide guidelines to design novel and potent inhibitors as antitubercular agents.

Antitubercular Agents↗
PubMed2002

Computer-aided design of selective COX-2 inhibitors: comparative molecular field analysis, comparative molecular similarity indices analysis, and docking studies of some 1,2-diarylimidazole derivatives.

Comparative molecular field analysis and comparative molecular similarity indices analysis were performed on 114 analogues of 1,2-diarylimidazole to optimize their cyclooxygenase-2 (COX-2) selective antiinflammatory activities. These studies produced models with high correlation coefficients and good predictive abilities. Docking studies were also carried out wherein these analogues were docked into the active sites of both COX-1 and COX-2 to analyze the receptor ligand interactions that confer selectivity for COX-2. The most active molecule in the series (53) adopts an orientation similar to that of SC-558 (4-[5-(4-bromophenyl)-3-trifluoromethyl-1H-1-pyrozolyl]-1-benzenesulfonamide) inside the COX-2 active site while the least active molecule (101) optimizes in a different orientation. In the active site, there are some strong hydrogen-bonding interactions observed between residues His90, Arg513, and Phe518 and the ligands. Additionally, a correlation of the quantitative structure-activity relationship data and the docking results is found to validate each other and suggests the importance of the binding step in overall drug action.

Binding Sites↗
PubMed2001

Crystal engineering in the gem-alkynol family: the key role of water in the structure of 2,3,5,6-tetrabromo-trans-1,4-diethynyl-cyclohexa-2,5-diene-1,4-diol dihydrate determined by X-ray and neutron diffraction at 150 K.

The structure of the title compound has been determined using low-temperature (150 K) single-crystal X-ray and neutron diffraction data. Crystals adopt the uncommon space group P4(2)/ncm and display a complex set of intermolecular interactions in which the water molecules play the crucial role: the water O-atom [O2(w)] accepts two hydrogen bonds and both water H atoms act as bifurcated donors. A set of O--H...O hydrogen bonds is formed around the 4(2) axis comprising (a) a cyclic tetrameric synthon involving four donor-H from two water molecules and two O(hydroxy) acceptors from two parent molecules, and (b) short discrete O(hydroxy)--H...O2(w) hydrogen bonds which link these tetramers along the c axis. Four Br...Br interactions [3.708 (1) A] form cyclic Br(4) tetramers around the 4 axis and are linked to the O--H...O system via O2(w)--H...Br bonds with H...Br = 2.995 (2) A. Finally, the O--H...O system is further linked to the parent molecules via C identical with C...H...O2(w) bonds of 2.354 (3) A. The supramolecular structure of the title hydrate is compared with that of the non-hydrated parent molecule, which also forms cyclic O--H...O bonded tetrameric synthons, and with its (non-hydrated) tetrachloro analogue, which forms cyclic tetrameric Cl(4) synthons [Madhavi, Desiraju et al. (2000b). Acta Cryst. B56, 1063--1070].

Journal Article↗
PubMed2001

Inclusion compounds of tetrakis(4-nitrophenyl)methane: C-H...O networks, pseudopolymorphism, and structural transformations.

Tetrakis(4-nitrophenyl)methane is a new host material with considerable structural adaptability over a range of solvents. The crystal structures of 14 of these solvates have been determined and classified into three groups. The diamondoid group, wherein the host molecules form a 2-fold interpenetrated diamondoid network structure, is unprecedented in that network connections are made exclusively with weak C-H...O and pi...pi interactions. This group consists of the solvates of THF, dioxane, nitrobenzene, 4-bromoanisole, anisole, phenetole, p-xylene, and chlorobenzene. The rhombohedral group, which is characterized by specific host.guest interactions of the C-H...O and halogen...O2N type, consists of the solvates of CHCl3 and CHBr3 and somewhat surprisingly DMF, which shows an unusual 3-fold disorder mimicking in part the shape and size of the haloform molecules though not their orientation. The third group comprises solvent-rich solvates of the host with mesitylene, collidine, and o-xylene with quite different crystal structures. The THF solvate was found to lose solvent over limited temperature ranges transforming reversibly from the diamondoid structure to the rhombohedral structure. A mechanism for this process is outlined. Material from which solvent has been removed by heating was also found to resolvate upon soaking in appropriate solvents. In summary, the title compound forms a host network that is partially robust and in part flexible. It is possible that this fluxional nature of the host network derives from the weakness of the connecting interactions.

Journal Article↗
PubMed2001

Crystal engineering of primary cubanecarboxamides: Repetitive formation of an unexpected N-H...O hydrogen-bonded network.

The unusual N-H.O hydrogen bond pattern in a family of primary cubanecarboxamides is described. 4-Chloro-1-cubanecarboxamide, 1, and the corresponding bromo and iodo derivatives, 2 and 3, form the "shallow-glide" hydrogen-bonded motif instead of the usual 5.1 A translated ribbon pattern, more characteristic of primary amides. This behavior is also seen, somewhat unexpectedly, for cubanecarboxamide, 4, but more or less unsurprisingly for 1,4-cubanedicarboxamide, 5. This repetitive occurrence of the same hydrogen bond pattern is of significance in crystal engineering wherein synthon robustness is measured in terms of such repetitivity. The cubyl group is directly responsible for the appearance of the shallow-glide motif in this family in preference to the 5.1 A translation pattern for two reasons: (1) steric--it is too large to fit in a 5.1 A translated structure and (2) electronic--its carbon acidity is sufficient to result in the appearance of C-H.O hydrogen bonds to the C=O group, disrupting any putative 5.1 A translated structure. Such a molecule --> supermolecule relationship is of value in crystal engineering strategies.

Journal Article↗
PubMed2001

Hydrogen bonding in two tetracyclic indole alkaloids.

3-Acetyl-1,6,7,12b-tetrahydroindolo[2,3-a]quinolizin-2(12H)-one, C17H16N2O2, consists of two symmetry-independent molecules and each forms a layered structure stabilized by N-H...O and C-H...O hydrogen bonds. In 3-acetyl-6,7-dihydroindolo[2,3-a]quinolizin-4(12H)-one monohydrate, C17H14)N2O2.H2O, the structure is stabilized by O-H...O, N-H...O and C-H...O hydrogen bonds, with the ordered water molecule playing a crucial role in the self-assembly. Contribution from the weak interactions to the strong hydrogen-bonded network is a common feature in both structures.

Crystallography, X-Ray↗
PubMed2000

The all-chemist.

Explore the source record for details and available documents.

Chemistry↗
PubMed2000

Racemic 1,2-diphenylbut-3-yn-2-ol.

Molecules of the title compound, C(16)H(14)O, are chiral and crystallize in space group P-4 with Z' = 2, and with one R and one S molecule in the asymmetric unit. The conformations of the phenyl rings in the two independent molecules differ slightly. Supramolecular organization in the crystal is via tetrameric O-H. H(O) hydrogen-bonded synthons formed separately by each conformer. These tetrameric synthons stack along the c axis via C[triple-bond]C-H.O(H) hydrogen bonds. The only link between the conformer stacks is provided by weaker C(methylene)-H and C(phenyl)-H interactions with pi(arene) density.

Journal Article↗
PubMed2000

4-Ethynyl-4-hydroxycyclohexan-1-one and 4-ethynyl-4-hydroxy-2,3,5, 6-tetramethylcyclohexa-2,5-dien-1-one.

The title compounds, C(8)H(10)O(2), (I), and C(12)H(14)O(2), (II), occurred as by-products in the controlled synthesis of a series of bis(gem-alkynols), prepared as part of an extensive study of synthon formation in simple gem-alkynol derivatives. The two 4-(gem-alkynol)-1-ones crystallize in space group P2(1)/c, (I) with Z' = 1 and (II) with Z' = 2. Both structures are dominated by O-H. O=C hydrogen bonds, which form simple chains in the cyclohexane derivative, (I), and centrosymmetric dimers, of both symmetry-independent molecules, in the cyclohexa-2,5-diene, (II). These strong synthons are further stabilized by C[triple-bond]C-H. O=C, C(methylene)-H.O(H) and C(methyl)-H.O(H) interactions. The direct intermolecular interactions between donors and acceptors in the gem-alkynol group, which characterize the bis(gem-alkynol) analogues of (I) and (II), are not present in the ketone derivatives studied here.

Journal Article↗
PubMed1998

Trimethyl isocyanurate and triethyl isocyanurate.

The crystal structures of trimethyl isocyanurate, C6H9N3O3, (1), and triethyl isocyanurate, C9H15N3O3, (2), contain topologically similar C--H...O hydrogen-bonded networks. In (1), there are two symmetry-independent molecules and each forms its own layer structure. In (2), two of the ethyl groups point one way with respect to the heterocyclic ring, while the third points in the opposite direction.

Crystallography, X-Ray↗
PubMed1993

C-H...O packing motifs in some cyclopenta[a]phenanthrenes.

An analysis has been made of the C-H...O interactions in cyclopenta[a]phenanthrenes, for which structural data on fifteen 15,16-dihydrocyclopenta[a]-phenanthren-17-ones are available. These compounds mostly contain only one O atom, a carbonyl group at the 17-position, and therefore the only groups available for interactions are C-H groups. In addition, the crystal structure of a second polymorph of the 11-ethyl derivative is described. M(r) = 260.33, Pbca, a = 17.012 (2), b = 21.042 (2), c = 7.6465 (6) A, V = 2737.2 (4) A, Z = 8, Dx = 1.264 Mg m-3, Cu K alpha, lambda = 1.5418 A, mu = 0.56 mm-1, F(000) = 1104, T = 295 K, final R = 0.090 for 1669 reflections above 2 sigma (F). The conformation of the ethyl group is gauche [C(12)-C(11)-C(18)-C(19) = 75.8 (7) degrees], differing from the cis value of -1.3 (5) degrees for the Pnaa form. The molecular distortion in the Pbca polymorph is also larger than that in the Pnaa polymorph; this distortion is evidenced by torsion angles (13-20 degrees) in the bay region and by an out-of-plane displacement (0.8 A) of the C atom of the methylene portion of the ethyl group [the C atom attached to C(11)]. Packing diagrams and intermolecular distances were analyzed for all the dihydrocyclopenta[a]phenanthrenes for which structural data are available. There appear to be three types of packing. The first type consists of a dimer herringbone formed by the interactions of two molecules by way of the ketone group and the C-H of C(12) of the adjacent ring. The second type of packing also involves a dimer but involves C-H and O-C groups at either ends of the molecule. The third type is a layer structure and involves compounds that crystallize with a unit-cell length of 7.5-7.6 A (or, in a very planar structure, 13.8 A). The translational stacking (approximately 4 A apart) found in polycyclic aromatic hydrocarbons is not observed in the crystal structures of these dihydrocyclopenta[a]-phenanthrenes because of the bulk of methyl or methylene groups and the dipole moment of the carbonyl group.

Crystallography, X-Ray↗
PubMedDate not supplied

Virtual screening of 4-anilinoquinazoline analogues as EGFR kinase inhibitors: importance of hydrogen bonds in the evaluation of poses and scoring functions.

Virtual Screening (VS) is a computational technique that allows selection and ranking of possible hits from a library of compounds. We have carried out VS on 128 selected EGFR kinase inhibitors with GOLD and LigandFit. From the experimental crystal structure of the erlotinib-EGFR complex, three key hydrogen bonds were identified as responsible for anchoring the ligand in the active site. These are of the N-H...N, O(w)-H...N, and C-H...O types. Failure to include the hydrogen-bonded water molecule that forms the O(w)-H...N bond leads to incorrect results. Of the three interactions, the C-H...O formed by an activated C-H group is the best conserved. On the basis of the efficacy of these hydrogen bonds, the poses were classified into one of three categories: close, shifted, and misoriented. In the VS context, all three interactions need to be modeled correctly so that correct poses and affinities are obtained, and this happens in ligands of the close variety. Cross scoring wherein the poses from one software are input into another for scoring and consensus scoring wherein the scores from various software packages are weighted are also helpful in obtaining better agreements.

Enzyme Inhibitors↗
PubMedDate not supplied

A virtual screening approach for thymidine monophosphate kinase inhibitors as antitubercular agents based on docking and pharmacophore models.

Docking and pharmacophore screening tools were used to examine the binding of ligands in the active site of thymidine monophosphate kinase of Mycobacterium tuberculosis. Docking analysis of deoxythymidine monophosphate (dTMP) analogues suggests the role of hydrogen bonding and other weak interactions in enzyme selectivity. Water-mediated hydrogen-bond networks and a halogen-bond interaction seem to stabilize the molecular recognition. A pharmacophore model was developed using 20 dTMP analogues. The pharmacophoric features were complementary to the active site residues involved in the ligand recognition. On the basis of these studies, a composite screening model that combines the features from both the docking analysis and the pharmacophore model was developed. The composite model was validated by screening a database spiked with 47 known inhibitors. The model picked up 42 of these, giving an enrichment factor of 17. The validated model was used to successfully screen an in-house database of about 500,000 compounds. Subsequent screening with other filters gave 186 hit molecules.

Antitubercular Agents↗
PubMedDate not supplied

Ligand coordinate analysis of SC-558 from the active site to the surface of COX-2: a molecular dynamics study.

We have performed a ligand coordinate analysis to monitor the movement of the inhibitor SC-558 from the active site of the COX-2 protein to the exterior using molecular dynamics techniques. This study provides an insight into the intermolecular interactions formed by the ligand during this journey. The published crystal structure of COX-2 with SC-558 in the active site (1cx2) was taken, and the ligand was moved incrementally in 13 steps. At each of these points on the path, exhaustive minimization and dynamics calculations were performed. The role of water was found to be important in these computations. An average structure was obtained from 250 conformations at each point and minimized. At each point on the path, the 10 lowest-energy conformations were also selected; a consideration of the average and lowest conformations provides fine details on the consistency of specific and strong interactions, and also on the geometry of the ligand. The movement of the ligand through the protein may be divided into three stages that are distinguished from each other because of energy and geometry discontinuities in both the ligand and the protein. The first of these covers the region between the active site and the point at 5.8 A from it. The second, which covers the distance between 8.2 and 10.0 A and is associated with maximum energetic and structural instability, is of critical importance. The third stage covers the distance between 10.5 A and the exterior and represents a stage of increasing hydration and expulsion of the ligand from the protein. Our results provide a confirmation for the existence of a shallow cavity near the protein surface in which the ligand is bound reversibly. By examining the residues that show maximum mobility, one obtains an idea of the gating mechanism that governs the entry and exit of the protein into or from the deep pocket that contains the active site. We note, however, that the variation of the root-mean-square deviation of all residues begins to increase almost as soon as the ligand leaves the active site, and even before there are any changes in the gate inter-residue distances. This loosening of the protein even before the gate opens might be a part of the enthalpy-entropy balance that accompanies the ligand's passage through the protein. Our results provide an energy profile of the ligand during its entry/exit into/from the protein and can, in principle, enable one to assess the residence time, which in turn may be associated or indirectly correlated with adverse cardiovascular side effects of nonsteroidal anti-inflammatory drugs. We believe that similar analyses for other selected COX-2-specific inhibitors will provide a measure (or prediction) of possible toxicity effects.

Binding Sites↗