Optimized Hydrophobic Interactions and Hydrogen Bonding at the Target-Ligand Interface Leads the Pathways of Drug-Designing

Weak intermolecular interactions such as hydrogen bonding and hydrophobic interactions are key players in stabilizing energetically-favored ligands, in an open conformational environment of protein structures. However, it is still poorly understood how the binding parameters associated with these interactions facilitate a drug-lead to recognize a specific target and improve drugs efficacy. To understand this, comprehensive analysis of hydrophobic interactions, hydrogen bonding and binding affinity have been analyzed at the interface of c-Src and c-Abl kinases and 4-amino substituted 1H-pyrazolo [3, 4-d] pyrimidine compounds.In-silico docking studies were performed, using Discovery Studio software modules LigandFit, CDOCKER and ZDOCK, to investigate the role of ligand binding affinity at the hydrophobic pocket of c-Src and c-Abl kinase. Hydrophobic and hydrogen bonding interactions of docked molecules were compared using LigPlot program. Furthermore, 3D-QSAR and MFA calculations were scrutinized to quantify the role of weak interactions in binding affinity and drug efficacy.The in-silico method has enabled us to reveal that a multi-targeted small molecule binds with low affinity to its respective targets. But its binding affinity can be altered by integrating the conformationally favored functional groups at the active site of the ligand-target interface. Docking studies of 4-amino-substituted molecules at the bioactive cascade of the c-Src and c-Abl have concluded that 3D structural folding at the protein-ligand groove is also a hallmark for molecular recognition of multi-targeted compounds and for predicting their biological activity. The results presented here demonstrate that hydrogen bonding and optimized hydrophobic interactions both stabilize the ligands at the target site, and help alter binding affinity and drug efficacy

MOLECULAR-ORBITAL CALCULATIONS ON FE4(CO)10(MU-CO)(MU-4-SE)2 AND FE3RU(CO)10(MU-CO)(MU-4-SE)2

Molecular orbital calculations using the extended Huckel program were carried out on Fe4(CO)10(mu-CO)(mu4-Se)2 and Fe3Ru(CO)10(mu-CO)(mu4-Se)2. On the basis of a molecular orbital description, binding energy, polarity and the metal-metal bond order were found to decrease on substitution of one Fe atom of Fe4(CO)10(mu-CO)(mu4-Se)2 by a Ru atom

Structural and Conformational Dependence of Optical Rotation Angles

The ability to compute and to interpret optical rotation angles of chiral molecules is of great value in assigning relative and absolute stereochemistry. The molar rotations for an indoline and an azetidine, as well as for menthol and menthone, were calculated using ab inito methods and compared to the experimental values. In one case the calculated rotation angle allowed the assignment of the absolute configuration of a heterocycle of unknown stereochemistry. The critical importance of Boltzmann averaging of conformers for reliable prediction of the optical rotation angle was established. Comparisons between static-field and time-dependent methods were made pointing to the limits and validity of the methods as electronic resonance is approached. A protocol analogous to population analysis was used to analyze atomic contributions to the rotation angle in specific conformers. The combination of atomic contribution maps and conformational analysis may provide an indirect tool to assist in three-dimensional structure determination

Synthetic and model computational studies of molar rotation additivity for interacting chiral centers: a reinvestigation of van't Hoff's principle.

When plane-polarized light impinges on a solution of optically active molecules, the polarization of the light that emerges is rotated. This simple phenomenon arises from the interaction of light with matter and is well understood, in principle, van't Hoff's rule of optical superposition correlates the molar rotation with the individual contributions to optical activity of isolated centers of asymmetry. This straightforward empirical additivity rule is rarely used for structure elucidation nowadays because of its limitations in the assessment of conformationally restricted or interacting chiral centers. However, additivity can be used successfully to assign the configuration of complex natural products such as hennoxazole A if appropriate synthetic partial structures are available. Therefore, van't Hoff's principle is a powerful stereochemical complement to natural products' total synthesis. The quest for reliable quantitative methods to calculate the angle of rotation a priori has been underway for a long time. Both classical and quantum methods for calculating molar rotation have been developed. Of particular practical importance for determining the absolute structure of molecules by calculation is the manner in which interactions between multiple chiral centers in a single molecule are included, leading to additive or non-additive optical rotation angles. This problem is addressed here using semi-empirical electronic structure models and the Rosenfeld equation

Optical rotation computation, total synthesis, and stereochemistry assignment of the marine natural product pitiamide A

We report the joint application of ab initio computations and total synthesis to assign the absolute configuration of a new natural product. The expected specific rotations of the (7S,10R)- and (7R,10R)-isomers of pitiamide A in a CHCl3 solvent continuum model were determined as +8 and - 39, respectively, by CADPAC calculations of the electric-dipole-magnetic- dipole polarizability tensor. Total syntheses of these two stereoisomers of the marine metabolite were achieved by a convergent strategy that utilized Evans' oxazolidinone alkylation, a novel water-accelerated modification of Negishi's zirconocene-catalyzed asymmetric carbometalation as well as an unusual segment condensation via Mitsunobu alkylation of a nosyl-activated amide. The experimental optical rotation measurements confirmed the results of the computational optical rotation predictions. On the basis of NMR comparisons, the configuration of pitiamide A was assigned as (7R,10R). These studies highlight the considerable structural significance of [α](D) data, but, because the optical rotation of the natural product was different from either synthetic diastereomer, our work serves also as an illustration of potential problems with obtaining accurate experimental [α](D) data for natural samples

Functionalization of a diacetylene on the mixed-chalcogenide compound fe2(co)6(mu-ste) - structural characterization of (co)6fe2(mu-sc(c-equivalent-to-cch3)=c(h)te)

The room-temperature reaction of the mixed-chalcogenide complex Fe2(CO)6(mu-STe) with the diacetylene CH3C=CC=CH forms the new compound (CO)6Fe2{mu-SC(C=CCH3)=C(H)Te}. The structure of (CO)6Fe2{mu-SC(C=CCH3)=C(H)Te} has been established by single-crystal X-ray diffraction methods: P1BAR, a = 6.587(2) angstrom, b = 10.689(3) angstrom, c = 11.067(3) angstrom, alpha = 92.74(2)-degrees, beta = 92.77(2)-degrees, gamma = 97.23(2)-degrees, V = 771(3) angstrom3, Z = 2, R = 5.6%, R(w) = 6.8%. Molecular orbital calculations have been performed on the four possible isomers of (CO)6Fe2{mu-SC(C=CCH3)=C(H)Te} which can be expected to form, and the formation of the experimentally found isomer has been rationalized

Hepatitis C virus NS5B polymerase: QM/MM calculations show the important role of the internal energy in ligand binding

The inter- and intramolecular interactions that determine the experimentally observed binding mode of the ligand (2Z)-2-(benzoylamino)-3-[4- (2-bromophenoxy)phenyl]-2-propenoate in complex with hepatitis C virus NS5B polymerase have been studied using QM/MM calculations. DFT-based QM/MM optimizations were performed on a number of ligand conformers in the protein-ligand complex. Using these initial poses, our aim is 2-fold. First, we identify the minimum energy pose. Second, we dissect the energetic contributions to this pose using QM/MM methods. The study reveals the critical importance of internal energy for the proper energy ranking of the docked poses. Using this protocol, we successfully identified three poses that have low RMSD with respect to the crystallographic structure from among the top 20 initially docked poses. We show that the most important energetic component contributing to binding for this particular protein-ligand system is the conformational (i.e., QM internal) energy. © 2008 American Chemical Society.link_to_subscribed_fulltex

Determination of the absolute configuration of 1,3,5,7-tetramethyl-1,3- dihydroindol-2-one by optical rotation computation

The absolute configuration of 1,3,5,7-tetramethyl-1,3-dihydroindol-2-one was determined by quantum chemical calculations of specific rotation angles with coupled-perturbed Hartree-Fock methods. The computation used molecular geometries obtained from ab initio calculations as well as from molecular mechanics and semi-empirical optimization. In addition to the dependence on geometry optimization strategies, the basis set dependence of the computed rotation angle was examined

Chiral Action at a Distance: Remote Substituent Effects on the Optical Activity of Calyculins A and B

(Equation Presented) Calyculins A and B differ only by the (E)- vs (Z)-configuration at C(2). Yet, they show a large difference in optical rotations. We demonstrate a new strategy that provides a physical analysis of this long-range chiro-optical effect by Boltzmann-averaged atomic contribution mapping. The polarizability characteristics of the CN substituent rather than the perturbation of the stereogenic centers or the introduction of dissymmetry into the polyene chain give rise to the remarkable difference in rotation angles

Determining absolute configuration in flexible molecules: A case study

Assigning absolute configuration of molecules continues to be a major problem. Determining absolute configuration in conformationally flexible systems is challenging, even for experts. Here, we present a case study in which we use a combination of molecular modeling, solution NMR, and X-ray crystallography to illustrate why it is difficult to use solution methods alone for configuration assignment. For the case examined, a comparison of calculated and experimental optical rotatory dispersion (ORD) data provides the most straightforward way to assign the absolute configuration