G. Narahari Sastry

Subtype Selectivity in Phosphodiesterase 4 (PDE4): A Bottleneck in Rational Drug Design

Subtype selectivity of phosphodiesterase 4 (PDE4) has been proposed to be the most salient feature for the development of drugs for asthma and inflammation. The present review provides an account of various strategies to overcome the side effects of the PDE4 inhibitors. Subtype selectivity and recent developments of molecular modeling approaches towards PDE4 were addressed using QSAR and docking, followed by a detailed structural analysis of more than three dozen available X-ray structures of PDE4B and PDE4D. Usually, the lack of a 3-dimensional structure of a target protein is a bottleneck for rational drug design approaches. However, in this case the availability of 39 X-ray structures along with co-crystals has not improved the therapeutic ratio of drugs through rational drug design approaches. The investigation of structures led to find significant variations in the M-loop region, which is the integral part of the active site of PDE4B and PDE4D. These differences can be accounted for by varying conformation of the Pro(430) residue and a Thr(436)/Asn(362) mutation in the M-loop that causes variations in adjacent residue properties and also the pattern of hydrogen-bonding interactions. The impact of the M-loop region on inhibitor binding has been further scrutinized by MOLCAD surfaces and hydrophobicity. These have shown that PDE4B is more hydrophobic in nature than PDE4D in the M-loop region. A review of the above aspects given the emphasis on a new PDE4 inhibitor which can access both metal and solvent pockets may possibly lead to ligands with enhanced potency. The lining of the Q2 pocket that involves the M-loop region may be considered for the design of potent subtype-selective inhibitors.

Novel Targets for Antiinflammatory and Antiarthritic Agents

Inflammation is a complex pathological condition associated with exaggerated human immune system involving various activated immune cells and bio-molecules. Treatment of inflammatory diseases particularly chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease etc. has been a big challenge for scientists as there are no safe drugs available for cure. Current therapeutic approaches to the treatment of inflammatory diseases are centered on cycloxygenase (both COX-1 and 2) proinflammatory enzymes but present available drugs of this category are associated with undesirable gastrointestinal and cardiovascular side effects. Recent scientific advents draw out the secrets of inflammation cache and understanding the involvement of several factors acting as stimulators or inhibitors thus opening new avenues for drug discoveries. Several bio-molecules such as proinflammatory cytokines, components of signal transduction and matrix degrading enzymes resolve inflammatory responses, might be new targets for treatment of chronic inflammatory diseases. This review gathers recent advances in drug research focusing interleukin-1, TNF-alpha, p38 kinase, c-Jun N-terminal kinase MAP kinase, NFkappaB, and matrix metalloproteinases. The biological roles of these inflammatory mediators are clearly understood thus offering new targets for design of novel inhibitors for incurable inflammatory diseases. This also provides an overview of the current nonsteroidal antiinflammatory agents.

Possibility of bond stretch isomerism in [Cp(CO)2M]2(μ-E) complexes (M=Mn, Re, Cr and W; E=S, Se and Te); a molecular orbital study

Abstract Extended Huckel calculations have been carried out on [Cp(CO)2M]2(μ-E) complexes (M ue5fb Mn, Re, Cr and W; E ue5fb S, Se and Te) in linear, bent and triangular geometries. The possibility of double well potential and consequent “bond stretch isomerism” in these complexes is analyzed. All the complexes with a 38 valence electron count (VEC) are calculated to have a minimum corresponding to the triangular geometry. The Mn and Cr complexes with a tellurido bridge have an additional minimum for the bent geometry; only the bent structure is known experimentally. The triangular isomers of these two complexes are marginally higher in energy, but separated by substantial barriers. The other M2E combinations studied adopt a triangular geometry. The difference in the behaviour between these complexes is explained by the fragment molecular orbital approach and by considering the atomic radii of the M and E species. Single point ab initio calculations using the LANL1MB basis set on [cp(CO)2M]2(μ-E) (M ue5fb Mn and Re; E ue5fb S, Se and Te) confirm the relative energy orderings produced by the extended Huckel calculations. The relation between the Mue5f8E bond orders and bond lengths and the extent of Main Group d-orbital participation is also analyzed. It is predicted that complexes with a VEC of 36 and 40 should adopt linear and bent geometries, respectively.

Synthetic strategies towards C60. Molecular mechanics and MNDO study on sumanene and related structures

Strain energies of the hydrocarbons derived from the fragments of C60 along the C5, C3 and C2 symmetry pathways indicate that the strain energy per carbon (Es) increases gradually along the C3 and C2 paths, but has a maximum at C40H10 along the C5 path. C21-Sumanene, 10, has been recognised as a leading fragment along C3 route with an inversion barrier of 24.2 kcal mol–1 and a bowl depth of 1.15 A at MNDO level. This contrasts with C20-corannulene, 6, which is a more shallow bowl with a lower inversion barrier. The bond alternation in the central six membered ring of sumanene resembles that of C60. The higher fragments en route to C60 are deep bowls with higher barriers for inversion. An approach to sumanene via a triphenylene derivative, 26, has been probed and an increase in strain through sequential placement of methylene bridges has been estimated, using MNDO and MM2 calculations. Synthetic routes to a doubly bridged triphenylene, 28, and schemes for further elaboration of 26a and sumanene derivative, 29, towards C60 are considered.

Electron transfer mechanisms: a mechanistic changeover induced by an intramolecular spacer in a model reaction of the NH3/C2H4˙+ pair

Computational evidence is reported for a reversal in the type of an electron transfer (ET) mechanism, induced by an intramolecular linkage of the donor (amine) and acceptor (cation radical) moieties via a single –CH2– spacer. An isotope effect probe is suggested to detect this mechanistic changeover.

An approach to functionalized cubanes. Regioselectivities and frontier molecular orbital analysis in the addition of dimethyl cyclobutadiene-1,2-dicarboxylate to quinones

4 + 2 Cycloaddition between dimethyl cyclobutadiene-1,2-dicarboxylate and benzoquinone, 4, gives 6, 7 and 8 in the ratio 15:4:1. Similarly naphthoquinone, 5, furnishes 9, 10 and 11 in the ratio 11:1:2. Formation of symmetrical adducts is predominent in both cases, Irradiation of major adducts 6 and 9 results in a cascade of photorearrangements. Semiempirical AM1 calculations are used to rationalize the regioselectivities.

Dyotropic rearrangements of Cp2Zr ligand complexes; a theoretical study

Abstract The dyotropic rearrangements in Cp 2 Zr ligand complexes such as Cp 2 Zr(X) (CH 2 SR) ( 3 ) have been studied by molecular orbital theory. The higher reactivity for the compound with X = Ph in comparison to that with X = Me, Cl, or CH 2 Ph is related to the energy match of MOs of the migrating fragment with those of the remaining fragment along an assumed reaction coordinate. The ease of conversion of Cp 2 Zr(C 4 H 3 O) 2 ( 5 ) into a zircona-cyclic species 6 can be similarly accounted for. Other substituents that should make the above reactions faster are suggested on the basis of the studies. A general discussion is presented on the migratory aptitudes and the difficulties involved in assigning migratory aptitudes that are independent of the specific reaction.

pH Dependence of a 310-Helix versus a Turn in the M-Loop Region of PDE4: Observations on PDB Entries and an Electronic Structure Study

Available X-ray crystal structures of phosphodiesterase 4 (PDE 4) are classified into two groups based on a secondary structure difference of a 310-helix versus a turn in the M-loop region. The only variable that was discernible between these two sets is the pH at the crystallization conditions. Assuming that at lower pH there is a possibility of protonation, thermodynamics of protonation and deprotonation of the aspartic acid, cysteine side chains, and amide bonds are calculated. The models in the gas phase and in the explicit solvent using the ONIOM method are calculated at the B3LYP/6-31+G* and B3LYP/6-31+G*:UFF levels of theory, respectively. The molecular dynamics (MD) simulations are also performed on the M-loop region of a 310-helix and a turn with explicit water for 10 ns under NPT conditions. The isodesmic equations of the various protonation states show that the turn containing structure is thermodynamically more stable when proline or cysteine is protonated. The preference for the turn structure on protonation (pH = 6.5-7.5) is due to an increase in the number of the hydrogen bonding and electrostatic interactions gained by the surrounding environment such as adjacent residues and solvent molecules.

Molecular electrostatic potential topographical studies on the structural motifs of C60

Molecular electrostatic potential topographical studies on the structural motifs of C60 reveal unusual features. Ethylene, [5]radialene and corannulene are predicted to be structural motifs present in C60. However, benzene does not fit into this framework. The double bonds in all the above molecules are activated upon pyramidalization at the carbon centre, the extent depending on the anisotropic environment of the conjugated carbon. The peripheral double bonds in corannulene are predicted to be more susceptible to electrophilic attack in comparison to the exocyclic double bonds of the five-membered ring.

Molecular orbital study of the structure and stability of transition metal polyhedral borane complexes. Position of bridging hydrogens

Abstract The dependence of bridging hydrogen atoms on terminal hydrogen positions in nido -metalloboranes has been studied using the model compounds B 4 H 8 X ( 6 , X = BH) and B 4 H 8 Fe(CO) 3 ( 1d ). Calculations on B 5 H 9 at both MNDO and extended Huckel levels have shown that the bridging hydrogen positions are controlled by the terminal hydrogen positions. Bridging hydrogen atoms might be observed above the B n plane (towards the cap), if the caps have sufficiently diffuse orbitals. Model studies at both MNDO and extended Huckel levels of B 4 H 8 X [X = BeH − , Li − and Fe(CO) 3 ] supported these results. The effects of increasing ring size from B 4 H 8 to B 5 H 10 are also studied. Suitable metal fragments for polyhedral borane ligands (rings) having five, six, seven, 11 and 13 vertex boron atoms can be selected using the ring—cap overlap match. Calculations have shown that B 6 H 6 4− ( 13 ) has more diffuse orbitals compared to B 11 H 11 4− ( 14 ) and B 13 H 13 4− ( 15 ). Compounds 14 and 15 preferred caps with less diffuse orbitals because of the rigidity of the ligands. The metal—ring boron distances in metalloboranes are controlled by this ring—cap compatibility. The concept of topological charge stabilization is also used in predicting the stabilities of various isomers of metalloboranes.