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At least 325 records · Page 18Linked to original sources
PubMed2005

Understanding and modulating cyclin-dependent kinase inhibitor specificity: molecular modeling and biochemical evaluation of pyrazolopyrimidinones as CDK2/cyclin A and CDK4/cyclin D1 inhibitors.

Cyclin-dependent kinases (CDKs) play a key role in regulating the cell cycle. The cyclins, their activating agents, and endogenous CDK inhibitors are frequently mutated in human cancers, making CDKs interesting targets for cancer chemotherapy. Our aim is the discovery of selective CDK4/cyclin D1 inhibitors. An ATP-competitive pyrazolopyrimidinone CDK inhibitor was identified by HTS and docked into a CDK4 homology model. The resulting binding model was consistent with available SAR and was validated by a subsequent CDK2/inhibitor crystal structure. An iterative cycle of chemistry and modeling led to a 70-fold improvement in potency. Small substituent changes resulted in large CDK4/CDK2 selectivity changes. The modeling revealed that selectivity is largely due to hydrogen-bonded interactions with only two kinase residues. This demonstrates that small differences between enzymes can efficiently be exploited in the design of selective inhibitors.

Amino Acid Sequence↗
PubMed2006

Molecular modeling of the calmodulin binding region of calcineurin.

The Homology module within Insight-II was used to model residues 374-420, sequences missing in the coordinates of resolved structure of the catalytic subunit of calcineurin. The modeling was done in two segments. The calmodulin binding region from residues 389 to 420 was modeled based on the structure of two other proteins having calmodulin binding domains with the same 1-8-14 structural motif as calcineurin. The link region (residues 374-389) between the calmodulin binding region and the solved core sequence was generated as a random loop and two residues at the C-terminal end of the sequence were added to the model using the EndRepair function within Homology. The model was refined using the Discover module of Insight-II with energy minimization. The Builder module was used to merge the modeled regions with the solved structure of calcineurin (residues 14-373). A final refinement step was done for the joined calcineurin model. From the model, it was predicted that the calmodulin and cyclophilin binding regions seem to be proximal. Biochemical experiments provided evidence that cyclosporin-A influenced calmodulin binding and activation of calcineurin consistent with overlapping binding regions.

Amino Acid Sequence↗
PubMed1993

Molecular modeling studies on the proposed NaCl-induced dimerization of Chromatium vinosum high-potential iron protein.

Previous work (Dunham, W.R., Hagen, W.R., Fee, J.A., Sands, R.H., Dunbar, J.B., Humblet, C. (1991) An investigation of Chromatium vinosum high-potential iron-sulfur protein by EPR and Mössbauer spectroscopy; evidence for a freezing-induced dimerization in NaCl solutions, Biochimica Biophysica Acta 1079, 253-262) suggested that under specific solution conditions and slow freezing times, samples of oxidized Chromatium vinosum (Cv) high-potential, iron-sulfur protein (HiPIP) form dimeric structures that exhibit characteristic spin-spin interaction in the EPR spectrum. In that study, it was also shown that two HiPIP molecules could approach each other along their Fe1-S4 axes to a distance of approximately 13-14 A, as required by an analysis of the spin-spin physics. This is made possible because of a flattened surface on one side of the molecule within which S4 may, depending on side-chain motions, interact with solvent (Carter, C.W., Jr., Kraut, J., Freer, S.T., Alden, R.A., Sieker, L.C., Adman, E.T., Jensen, L.H. (1972) A comparison of Fe4S4 clusters in high potential iron protein and in ferredoxin, Proc. Natl. Acad. Sci. USA 69, 3527-3529). Here we describe a computer generated, hypothetical model of this proposed dimeric structure which suggests an energetically favorable interaction between two Cv HiPIP molecules and could account for the experimental observations. Two Cv HiPIP molecules brought together along their Fe1-S4 axes and maintained at a center-to-center distance of 14 A can be rotated with respect to each other so as to create complementary interactions between two glutamine residues, two phenylalanine residues, and two leucine residues, and an energetically unfavorable interaction between two arginine residues. Energy minimization calculations using the program XPLOR indicate that this arrangement may provide an overall energetically favorable interaction between the two HiPIP molecules that is strengthened by site-specific binding of Na and Cl ions.

Amino Acid Sequence↗
PubMed1984

Molecular models for the interaction of the anti-tumour drug nogalamycin with DNA.

Computer graphics and non-bonded energy calculations have been used to model the intercalative binding of the anti-tumour antibiotic nogalamycin, to double-stranded DNA. The drug is predicted to bind preferentially to A-T rich sites. Specific hydrogen bonds to the exocyclic amino group of adenine bases on the 3' side of an intercalative site have been found by the modelling procedure.

DNA↗
PubMed1990

Conformational features of C-glycosyl compounds: crystal structure and molecular modelling of "methyl C-gentiobioside".

The crystal of "methyl C-gentiobioside" (methyl 8,12-anhydro-6,7-dideoxy-D-glycero-D-gulo-alpha-D-gluco-trideca pyranoside) (C14H26O10) is triclinic, space group P1, with a = 1.0181 (6) nm, b = 0.8093 (5) nm, c = 0.5066 (4) nm, alpha = 96.03 (5) degrees, beta = 99.94 (5) degrees, gamma = 90.85 (5) degrees. The two D-glucose residues have the 4C1 conformation. The orientation of the beta-(1----6) linkage is characterized by torsion angles phi = 55.9 degrees, psi = 175.1 degrees, and omega = -63.9 degrees. The orientation of the primary hydroxyl group at the non-reducing residue is gauche-trans (omega' = -53.6 degrees). There is no intramolecular hydrogen bond. Molecules are held together by a network of hydrogen bonds involving all of the hydroxyl groups. This crystal structure is the first experimental characterization of a "C-disaccharide". Unlike methyl gentiobioside, which has a high level of conformational flexibility, the "C-disaccharide" has a restricted flexibility. Each of the low-energy conformers in vacuo has a value of phi centered about 60 degrees, in agreement with the solid state conformation, and the exo-anomeric effect is no longer predominant.

Carbohydrate Conformation↗
PubMed1986

Origins of stereospecificity in DNA damage by anti-benzo[a]pyrene diol-epoxides. A molecular modelling study.

A general computational procedure for the modelling of intercalated DNA-ligand complexes has been developed, and is used here to model intercalated complexes of the (+)-anti and (-)-anti enantiomers of benzo[a]pyrene diol-epoxide (BPDE) with cytosine-3',5'-guanosine double-stranded DNA sequences (dCpG). Results are presented indicating differences between the behaviours of the two enantiomers which have implications for the understanding of the stereospecificity of DNA strand breakage by benzo[a]pyrene diol-epoxides.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1996

Molecular modelling of human gastric alcohol dehydrogenase (class IV) and substrate docking: differences towards the classical liver enzyme (class I).

A three-dimensional model of the human class IV alcohol dehydrogenase has been calculated based upon the X-ray structure of the class I enzyme. As judged from the model, the substrate-binding site is wider than in class I, compatible with the differences in substrate specificities and the large difference in Km value for ethanol. Substrate docking performed for the class I structure and the class IV model show all-trans-retinol and 11-cis-retinol to bind better to the class IV enzyme. The calculations also indicate that 16-hydroxyhexadecanoic acid binds in a different manner for the two enzyme classes. A simulation of coenzyme-binding indicates that the adenine ring of the coenzyme might be differently bound in class IV than in class I, decreasing the interactions with Asp-223 which is compatible with the higher k(cat) values for class IV.

Alcohol Dehydrogenase↗
PubMed1991

Molecular models for recognition and activation at the benzodiazepine receptor: a review.

In this minireview an overview description of the different pharmacophores that have been proposed for the benzodiazepine receptor is presented. The methodology as well as the experimental information used in the development of each model will be described. Finally, the new experimental discoveries that are likely to affect the models presented are briefly indicated.

Animals↗
PubMed1991

Molecular modeling of antibody combining sites.

Each of the six CDRs of Gloop2 is shown with the modeled structure in. Overall, the results obtained using the combined algorithm are similar in accuracy to those achieved using the canonical method of Chothia et al. However, the canonical method is limited to those loops where the key residues identified by Chothia are present. With the number of antibody structures currently available, it is not possible to classify CDR-H3 into canonical ensembles. Additionally, a small percentage of examples in the remaining CDRs do not match the current canonical classifications and the protein engineer may well wish to mutate the key residues, precluding the use of Chothia's method for modeling the resulting conformation. Thus the best approach appears to be to use Chothia's method (at least to model the backbone conformation) when the loop to be modeled is represented in the database of canonical structures. Any other loops, either unrepresented among the known canonicals (including CDR-H3), or where mutations have been made to the key residues, may then be modeled by the combined algorithm presented here.

Algorithms↗
PubMed1991

Molecular modeling of 5-HT3 receptor ligands.

Ligands of various chemical classes (e.g., indoles, indazoles, benzamides, carbazoles, and quinolines) have demonstrated high affinity for the 5-HT3 receptor in radiolabeled ligand-binding studies, and have shown 5-HT3 receptor antagonistic activity in functional assays which utilize the excitatory effects of 5-HT on enteric neurons and autonomic afferents. Several 5-HT3 antagonists are currently being evaluated for potential use in the treatment of migraine, schizophrenia, and anxiety, and a few have already demonstrated high efficacy as antiemetics in cancer chemotherapy. The purpose of this presentation is to highlight the significant structure-affinity relationships (SAFIR) and common geometrical features among 5-HT3 receptor ligands, and to describe the three-dimensional pharmacophore for the 5-HT3 recognition site derived from computational techniques. The chemical template containing the recognition elements (functional groups) for the 5-HT3 receptor are: an aromatic or heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center, interrelated by well-defined distances. Two "binding shapes" or "active shapes" for 5-HT3 ligands have been identified from detailed conformational analyses.

Animals↗
PubMed1983

Molecular model of a eucaryotic transcription complex: functions and movements of influenza P proteins during capped RNA-primed transcription.

We present a model for the functions and movements of the influenza virus P proteins (PB1, PB2, and PA) as they transcribe the virion RNAs (vRNAs) into messenger RNAs (mRNAs). Using ultraviolet-light-induced crosslinking, we show that the P proteins as a complex move from the 3' ends of the vRNA templates down the elongating mRNAs. PB2 binds the cap 1 structure of heterologous RNAs, which are cleaved to generate capped primer fragments. PB1, initially found at the first residue added onto the primer, moves to the 3' ends of the growing mRNA chains, indicating that it most likely catalyzes each nucleotide addition. PA and PB2 move down the growing chains in concert with PB1. PB2 is also associated with the cap during the first 11-15 nucleotides of chain growth, but then dissociates from the cap as the P protein complex moves further down the mRNA chains.

Base Sequence↗