Shape group studies of molecular similarity: relative shapes of Van der Waals and electrostatic potential surfaces of nicotinic agonists

In drug design, the usual strategy involves characterizing and comparing the shapes of molecules. We apply a simple method to accomplish this goal: determining the symmetry-independent shape groups (homology groups of algebraic topology) of a molecular surface.In this paper, we have adapted the method to describing the interrelation between Van der Waals and electrostatic potential surfaces. We describe rigorously the shape features in a series of molecules by using specific ranges of electrostatic potential over a Van der Waals surface. We consider a series of four nicotinic agonists as an example and discuss their expected activities as potential drugs on the basis of the shape similarities found.     

Binding to δ and μ opioid receptors by deltorphin I/II analogues modified at the Phe and Asp/Glu side chains: a report of 32 new analogues and a QSAR study

The synthesis and binding affinities of 32 X³Gly⁴ dual-substitution analogues of the natural opioid heptapeptides deltorphin I and II are reported. A multiple regression QSAR analysis was performed using those results along with literature data for the X³Asp⁴ and Phe³X⁴ side chain analogues. Fitting to a three-term potential well model with hydrophobic and van der Waals attraction terms and a steric repulsion term indicates that the δ and μ receptor sites for binding the residue three side chain are similar, and that the binding interaction is primarily van der Waals and secondarily hydrophobic. Further analysis indicates that both sites are more constrained with respect to side chain length than width or thickness, and the μ site appears to be somewhat larger. A binding model consistent with these findings pictures the native third residues Phe ring laying on a step notched out of the receptor surface, pointing toward the back (riser) of the step, and sandwiched between the receptor and ligand. However, the binding sites for the residue four side chains are quite different on δ and μ receptors. Binding to the δ site appears to involve both electrostatic attraction (probably to a partial positive charge) and van der Waals attraction, but not necessarily hydrogen bonding, and more constraint with respect to side chain length than width or thickness. In contrast, there is no evidence for any kind of binding attraction between the side chain of residue four and the μ site, which acts more as steric repulsion site, as though the space that is a pocket on the δ receptor is filled in on the μ receptor. A regression model based only on steric repulsion by van der Waals bulk and/or the effective bulk of a hydration layer accounts for over 80% of the residue four related variation in μ affinity.

Abstract

Thirty-two new X³Gly⁴ analogues of deltrophin I/II opioid peptides are described. A QSAR study of the X³Gly⁴, X³Asp⁴, and Phe³X⁴ analogue series using a potential well model reveals the roles of hydrophobic, van der Waals, electrostatic, hydrogen bonding and steric interactions in δ and μ receptor binding of X³ and X⁴ side chains.     

An insight into the inhibitory selectivity of 4-(Pyrazol- 4-yl)-pyrimidines to CDK4 over CDK2

Revealing selectivity mechanism of cyclin-dependent kinases (CDK) and their inhibitors is an important issue to develop potential anticancer drugs. The substituted 4-(Pyrazol-4-yl)-pyrimidines are potent inhibitors of CDK4 but not of the highly homologous CDK2. In order to reveal the inhibitory selectivity of these inhibitors to CDK4 over CDK2, we select one of substituted 4-(Pyrazol-4-yl)-pyrimidines as a representative (marked as A1 hereunder) and perform molecular docking, molecular dynamics simulations and binding free energy analysis for CDK4/A1 and CDK2/A1, respectively. The electrostatic and van der Waals (vdW) interactions of the A1 inhibitor with CDK4/CDK2 are discussed. The computed binding free energies based on the MM-PBSA method are consistent with experimental bioactivity ranking of A1 inhibitor to CDK4/CDK2. On the other hand, the conformational characteristics of CDK2 and CDK4 induced by A1 inhibitor are analysed and revealed. Results demonstrate that the vdW interactions considerably contribute to binding of CDK4/CDK2 with A1 inhibitor and are similar in size. The hydrogen bonding between A1 inhibitor and CDK4/CDK2 is considerably favourable to the binding, in which the hydrogen bond between the NH group of the pyrazole group of A1 and the residue Asp158 of CDK4 plays a crucial role in inhibitory selectivity of A1 inhibitor to CDK4 over CDK2. The electrostatic interaction energy differences between the corresponding residues of CDK4/A1 and CDK2/A1 confirm the above inference. The conformational changes of CDK2 and CDK4 induced by A1 inhibitor influence the selectivity of A1 inhibitor to CDK4/CDK2.     

Probing the electronic structures and properties of neutral and anionic ScSi n (0,−1) (n = 1–6) clusters using ccCA-TM and G4 theory

We apply molecular docking, molecular dynamics (MD) simulation, and binding free energy calculation to investigate and reveal the binding mechanism between five xanthine inhibitors and DPP-4. The electrostatic and van der Waals interactions of the five inhibitors with DPP-4 are analyzed and discussed. The computed binding free energies using MM-PBSA method are in qualitatively agreement with experimental inhibitory potency of five inhibitors. The hydrogen bonds of inhibitors with Ser630 and Asp663 can stabilize the inhibitors in binding sites. The van der Waals interactions, especially the key contacts with His740, Asn710, Trp629, and Tyr666 have larger contributions to the binding free energy and play important roles in distinguishing the variant bioactivity of five inhibitors.     

Theoretical Study of Antagonists and Inhibitors of Mammalian Adenosine Deaminase: I. Adenosine and Its Aza- and Deazaanalogues

Aza- and deazaanalogues of adenosine, including their 1-protonated forms (except for that of 1-deazaadenosine), were studied by computer computation to find a relationship between their molecular structures and substrate properties for the mammalian adenosine deaminase. The atomic charge distribution and maps of the electrostatic potential around their van der Waals molecular surface were calculated for these compounds using the ab initio STO-3G method. The conformational studies are carried out by the MM⁺ method of molecular mechanics. The mechanism that determines the substrate selectivity of mammalian adenosine deaminase is discussed.     

Theoretical study of antagonists and inhibitors of mammalian adenosine deaminase. I. Adenosine and its aza- and deaza-analogs

Aza- and deazaanalogues of adenosine, including their 1-protonated forms (except for that of 1-deazaadenosine), were studied by computer computation to find a relationship between their molecular structures and substrate properties for the mammalian adenosine deaminase. The atomic charge distribution and maps of the electrostatic potential around their van der Waals molecular surface were calculated for these compounds using the ab initio STO-3G method. The conformational studies were carried out by the MM+ method of molecular mechanics. The mechanism that determines the substrate selectivity of mammalian adenosine deaminase is discussed. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2002, vol. 28, no. 4; see also http://www.maik.ru.     

Molecular similarity analysis between insect juvenile hormone and N, N-diethyl-m-toluamide (DEET) analogs may aid design of novel insect repellents

Molecular similarity analysis of stereoelectronic properties between natural insect juvenile hormone (JH), -a synthetic insect juvenile hormone mimic (JH-mimic, undecen-2-yl carbamate), and N, N-diethyl-m-toluamide (DEET) and its analogs reveals similarities that may aid the design of more efficacious insect repellents and give a better insight into the mechanism of repellent action. The study involves quantum chemical calculations using the AM1 semi-empirical computational method enabling a conformational search for the lowest and most abundant energy conformers of JH, JH-mimic, and 15 DEET compounds, followed by complete geometry optimization of the conformers. Similarity analyses of stereoelectronic properties such as structural parameters, atomic charges, dipole moments, molecular electrostatic potentials, and highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies were performed on JH, JH-mimic and the DEET compounds. The similarity of stereoelectronic attributes of the amide/ester moiety, the negative electrostatic potential regions beyond the van der Waals surface, and the large distribution of hydrophobic regions in the compounds appear to be the three important factors leading to a similar interaction with the JH receptor. The similarity of electrostatic profiles beyond the van der Waals surface is likely to play a crucial role in molecular recognition interaction with the JH receptor from a distance. This also suggests electrostatic bioisosterism of the amide group of the DEET compounds and JH-mimic and, thus, a model for molecular recognition at the JH receptor. The insect repellent property of the DEET analogs may thus be attributed to a conflict of complementarity for the JH receptor binding sites.     

Molecular dynamics and free energy analysis of neuraminidase-ligand interactions

We report molecular dynamics calculations of neuraminidase in complex with an inhibitor, 4-amino-2-deoxy-2,3-didehydro-N-acetylneuraminic acid (N-DANA), with subsequent free energy analysis of binding by using a combined molecular mechanics/continuum solvent model approach. A dynamical model of the complex containing an ionized Glu119 amino acid residue is found to be consistent with experimental data. Computational analysis indicates a major van der Waals component to the inhibitor-neuraminidase binding free energy. Based on the N-DANA/neuraminidase molecular dynamics trajectory, a perturbation methodology was used to predict the binding affinity of related neuraminidase inhibitors by using a force field/Poisson-Boltzmann potential. This approach, incorporating conformational search/local minimization schemes with distance-dependent dielectric or generalized Born solvent models, correctly identifies the most potent neuraminidase inhibitor. Mutation of the key ligand four-substituent to a hydrogen atom indicates no favorable binding free energy contribution of a hydroxyl group; conversely, cationic substituents form favorable electrostatic interactions with neuraminidase. Prospects for further development of the method as an analysis and rational design tool are discussed.     

Conformation of (1→3)-α-D-Glucan Tribenzoate

The molecular conformation of (1→3)-α-D-glucan tribenzoate (TBG) was studied by X-ray diffraction measurements coupled with a conformational analysis. Although the fiber pattern obtained was of very low crystallinity, the presence of a meridional reflection at the 5th layer line indicated that the TBG molecule took a five-fold helical conformation with a 19.63 A fiber repeat. A conformational analysis on the five-fold helix, which was done by calculating van der Waals’ repulsion energy between non-bonded atoms comprising the TBG chain, suggested that the most preferable energy-based conformation was –5/1, a left-handed five-fold helix.     

Predicting protein interaction sites: binding hot-spots in protein-protein and protein-ligand interfaces

MOTIVATION: Protein assemblies are currently poorly represented in structural databases and their structural elucidation is a key goal in biology. Here we analyse clefts in protein surfaces, likely to correspond to binding 'hot-spots', and rank them according to sequence conservation and simple measures of physical properties including hydrophobicity, desolvation, electrostatic and van der Waals potentials, to predict which are involved in binding in the native complex. RESULTS: The resulting differences between predicting binding-sites at protein-protein and protein-ligand interfaces are striking. There is a high level of prediction accuracy (< or =93%) for protein-ligand interactions, based on the following attributes: van der Waals potential, electrostatic potential, desolvation and surface conservation. Generally, the prediction accuracy for protein-protein interactions is lower, with the exception of enzymes. Our results show that the ease of cleft desolvation is strongly predictive of interfaces and strongly maintained across all classes of protein-binding interface.     

Analytically defined surfaces to analyze molecular interaction properties

Molecular surfaces are widely used for characterizing molecules and displaying and quantifying their interaction properties. Here we consider molecular surfaces defined as isocontours of a function (a sum of exponential functions centered on each atom) that approximately represents electron density. The smoothness is advantageous for surface mapping of molecular properties (e.g., electrostatic potential). By varying parameters, these surfaces can be constructed to represent the van der Waals or solvent-accessible surface of a molecular with any accuracy. We describe numerical algorithms to operate on the analytically defined surfaces. Two applications are considered: (1) We define and locate extremal points of molecular properties on the surfaces. The extremal points provide a compact representation of a property on a surface, obviating the necessity to compute values of the property on an array of surface points as is usually done; (2) a molecular surface patch or interface is projected onto a flat surface (by introducing curvilinear coordinates) with approximate conservation of area for analysis purposes. Applications to studies of protein-protein interactions are described.     

Theoretical study of antagonists and inhibitors of mammalian adenosine deaminase. II. Isomeric aza-deazaanalogues of adenosine

Isomeric aza-deazaanalogues of adenosine and their N1-protonated forms (except for that of 8-aza-1-deazaadenosine) were studied by computer modeling to find a relationship between their molecular structures and the properties as substrates for the mammalian adenosine deaminase. The atomic charge distribution and maps of the electrostatic potential around their van der Waals molecular surface were calculated using the ab initio STO-3G method. The conformational studies were carried out by the MM+ method of molecular mechanics. The previously proposed mechanism of the substrate acceptance in the active site of mammalian adenosine deaminase was refined, and the potential substrate properties were predicted for two previously unstudied adenosine analogues, 5-aza-9-deazaadenosine and 8-aza-3-deazaadenosine.     

Molecular mechanical perspective on halogen bonding

The nature and strength of halogen bonding in halo molecule-Lewis base complexes were studied in terms of molecular mechanics using our recently developed positive extra-point (PEP) approach, in which the σ-hole on the halogen atom is represented by an extra point of positive charge. The contributions of the σ-hole (i.e., positively charged extra point) and the halogen atom to the strength of this noncovalent interaction were clarified using the atomic parameter contribution to the molecular interaction (APCtMI) approach. The molecular mechanical results revealed that the halogen bond is electrostatic and van der Waals in nature, and its strength depends on three types of interaction: (1) the attractive electrostatic interaction between the σ-hole and the Lewis base, (2) the repulsive electrostatic interaction between the negative halogen atom and the Lewis base, and (3) the repulsive/attractive van der Waals interactions between the halogen atom and the Lewis base. The strength of the halogen bond increases with increasing σ-hole size (i.e., magnitude of the extra-point charge) and increasing halogen atom size. The van der Waals interaction's contribution to the halogen bond strength is most favorable in chloro complexes, whereas the electrostatic interaction is dominant in iodo complexes. The idea that the chloromethane molecule can form a halogen bond with a Lewis base was revisited in terms of quantum mechanics and molecular mechanics. Although chloromethane does produce a positive region along the C-Cl axis, basis set superposition error corrected second-order M?ller-Plesset calculations showed that chloromethane-Lewis base complexes are unstable, producing halogen-Lewis base contacts longer than the sum of the van der Waals radii of the halogen and O/N atoms. Molecular mechanics using the APCtMI approach showed that electrostatic interactions between chloromethane and a Lewis base are unfavorable owing to the high negative charge on the chlorine atom, which overcomes the corresponding favorable van der Waals interactions.     

Modeling of nucleic acid complexes with cationic ligands: a specialized molecular mechanics force field and its application.

A potential energy force field designed for modeling nucleic acids and particularly their complexes with cationic ligands is presented. The force field is a modified version of that developed by Weiner, S.J., Kollman, P.A., Nguyen, D.T. and Case, D.A.,J. Comp. Chem. 7,230-252 (1986) and is based upon the use of a distance dependent dielectric constant, epsilon = 4rij, and partially neutralized phosphates to represent solvent and counterion. Changes from the Weiner et al. force field include additional atom types and modifications to van der Waals, electrostatic, hydrogen bonding and torsional parameters. Molecular modeling test cases of the force field are presented for a number of simple small molecules, as well as uracil and benzene dimerization, thymine-adenine and cytosine-guanine base pair formation, and adenosine/deoxyadenosine pseudorotation. Several DNA and RNA oligomers and DNA/RNA intercalation complexes with ethidium are also modeled with the force field. In all cases, the modeling results compare favorably with available experimental results. Additionally, conformational trends observed experimentally for nucleic acids by NMR and X-ray crystallographic techniques are reproduced. The modeling results for ethidium intercalation indicate a complex in which the favorable interactions are primarily van der Waals contacts, and in which electrostatic interactions are a relatively minor component. We feel the force field is particularly useful for molecular mechanics aided drug design, and an analysis of modeling results with respect to design of drugs which bind selectively to RNA is presented.     

Theoretical Study of Antagonists and Inhibitors of Mammalian Adenosine Deaminase: II. Isomeric Aza-deazaanalogues of Adenosine

Isomeric aza-deazaanalogues of adenosine and their N1-protonated forms (except for that of 8-aza-1-deazaadenosine) were studied by computer modeling to find a relationship between their molecular structures and the properties as substrates for the mammalian adenosine deaminase. The atomic charge distribution and maps of electrostatic potential around their van der Waals molecular surface were calculated using the ab initioSTO-3G method. The conformational studies were carried out by the MM⁺ method of molecular mechanics. The previously proposed mechanism of the substrate acceptance in the active site of mammalian adenosine deaminase was refined, and the potential substrate properties were predicted for two previously unstudied adenosine analogues, 5-aza-9-deazaadenosine and 8-aza-3-deazaadenosine.     

Prediction of fluorine chemical shifts in proteins

Molecular dynamics calculations have been used in an effort to estimate the change in fluorine nmr shielding when a fluorine nucleus enters the tertiary structure of a protein. Considerations of the possible interactions that can define the shift parameter change suggest that van der Waals interactions are the leading determinant of fluorine shifts in proteins, although aromatic ring currents, other magnetic anisotropies, and electrostatic field effects could result in shift distinctions of 1 ppm or smaller. Results of our studies of a fluorine-containing analogue of the ribonuclease A S-protein/S-peptide complex indicate that static structures such as those implied by crystallographic data lead to overestimates of the magnitude of the van der Waals shielding term; molecular dynamics simulations provide indications of the effects of conformational averaging in defining this term. The treatment used predicts the correct direction of the shift change when the fluorine enters this protein environment from aqueous solution and, with an experimentally supported choice of adjustable parameters, gives agreement with the magnitude of the shift.     

Comparative binding energy analysis of the substrate specificity of haloalkane dehalogenase from Xanthobacter autotrophicus GJ10

Comparative binding energy (COMBINE) analysis was conducted for 18 substrates of the haloalkane dehalogenase from Xanthobacter autotrophicus GJ10 (DhlA): 1-chlorobutane, 1-chlorohexane, dichloromethane, 1,2-dichloroethane, 1,2-dichloropropane, 2-chloroethanol, epichlorohydrine, 2-chloroacetonitrile, 2-chloroacetamide, and their brominated analogues. The purpose of the COMBINE analysis was to identify the amino acid residues determining the substrate specificity of the haloalkane dehalogenase. This knowledge is essential for the tailoring of this enzyme for biotechnological applications. Complexes of the enzyme with these substrates were modeled and then refined by molecular mechanics energy minimization. The intermolecular enzyme-substrate energy was decomposed into residue-wise van der Waals and electrostatic contributions and complemented by surface area dependent and electrostatic desolvation terms. Partial least-squares projection to latent structures analysis was then used to establish relationships between the energy contributions and the experimental apparent dissociation constants. A model containing van der Waals and electrostatic intermolecular interaction energy contributions calculated using the AMBER force field explained 91% (73% cross-validated) of the quantitative variance in the apparent dissociation constants. A model based on van der Waals intermolecular contributions from AMBER and electrostatic interactions derived from the Poisson-Boltzmann equation explained 93% (74% cross-validated) of the quantitative variance. COMBINE models predicted correctly the change in apparent dissociation constants upon single-point mutation of DhlA for six enzyme-substrate complexes. The amino acid residues contributing most significantly to the substrate specificity of DhlA were identified; they include Asp124, Trp125, Phe164, Phe172, Trp175, Phe222, Pro223, and Leu263. These residues are suitable targets for modification by site-directed mutagenesis.