The search for orally active medications through combinatorial chemistry

Fecik, Robert; Frank, Kristine E.; Gentry, Elmer J.; Menon, Sanjay; Mitscher, Lester A.; Telikepalli, Hanumaiah

doi:10.1002/(sici)1098-1128(199805)18:3<149::aid-med2>3.0.co;2-x

Cited by 75 publications

(31 citation statements)

References 97 publications

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“…Evans et al [79] in 1988 first used the term ''privileged structure'' to describe a structure that is capable of binding to a relatively large number of receptors, in reference to this benzodiazepine scaffold. Interestingly, of the 14 spatial matches between the benzodiazepine scaffold and the loop structure, 11 belong to the b-turn branch of the loop, in agreement with the previous report that benzodiazepine scaffold is b-turn mimetic [44,79]. It was gratifying that the loop clusters were able to identify the prototypical privileged substructure .…”

Section: Biologically Relevant Descriptorssupporting

confidence: 88%

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Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

Tran

Kulis

Long

et al. 2010

J Comput Aided Mol Des

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Medicinal chemists synthesize arrays of molecules by attaching functional groups to scaffolds. There is evidence suggesting that some scaffolds yield biologically active molecules more than others, these are termed privileged substructures. One role of the scaffold is to present its side-chains for molecular recognition, and biologically relevant scaffolds may present side-chains in biologically relevant geometries or shapes. Since drug discovery is primarily focused on the discovery of compounds that bind to proteinaceous targets, we have been deciphering the scaffold shapes that are used for binding proteins as they reflect biologically relevant shapes. To decipher the scaffold architecture that is important for binding protein surfaces, we have analyzed the scaffold architecture of protein loops, which are defined in this context as continuous four residue segments of a protein chain that are not part of an α-helix or β-strand secondary structure. Loops are an important molecular recognition motif of proteins. We have found that 39 clusters reflect the scaffold architecture of 89% of the 23,331 loops in the dataset, with average intra-cluster and inter-cluster RMSD of 0.47 and 1.91, respectively. These protein loop scaffolds all have distinct shapes. We have used these 39 clusters that reflect the scaffold architecture of protein loops as biological descriptors. This involved generation of a small dataset of scaffold-based peptidomimetics. We found that peptidomimetic scaffolds with reported biological activities matched loop scaffold geometries and those peptidomimetic scaffolds with no reported biologically activities did not. This preliminary evidence suggests that organic scaffolds with tight matches to the preferred loop scaffolds of proteins, implies the likelihood of the scaffold to be biologically relevant.

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Section: Biologically Relevant Descriptorssupporting

confidence: 88%

“…Three b-turn mimetics, 14 [37], 15 [37,41,[44][45][46], and 16 [37,44] contain a benzodiazepine scaffold. These mimetics match the loops with an average RMSD of 0.41 0.45 and 0.45, respectively ( Table 2).…”

Section: Biologically Relevant Descriptorsmentioning

confidence: 99%

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

Tran

Kulis

Long

et al. 2010

J Comput Aided Mol Des

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“…natorial chemistry 1) and high throughput screening for pharmacological activity (HTS) [2][3][4] have produced enormous numbers of drug candidates within a short time period and subsequently have necessitated the development of rapid methods for assessment of their pharmacokinetic and toxicological properties, especially oral absorption and metabolism. However, a number of both known and unknown factors influence the overall bioavailability of orally administered drugs, 5,6) and therefore rapid assessment has been thought to be impossible.…”

mentioning

confidence: 99%

Molecular and Pharmacokinetic Properties of 222 Commercially Available Oral Drugs in Humans.

Sakaeda

Okamura

Nagata

et al. 2001

Biological & Pharmaceutical Bulletin

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This study was performed to determine the exclusion criteria that differentiate poorly absorbed drugs from good drug candidates, and to accelerate drug development by exclusion of unnecessary assessment. The molecular and pharmacokinetic properties of 222 commercially available oral drugs were tabulated and their correlations were analyzed. The exclusion criteria obtained were 1) a molecular weight of more than 500, and 2) a ClogP value of more than 5. Exceptions to molecular weight criteria were compounds with a sugar moiety, high atomic weight, and large cyclic structure. It was also suggested that being a substrate for MDR1 (P-glycoprotein) does not always result in poor bioavailability, and that drug development by chemical modification of a seed or lead compound with quantitative structure activity relationship analysis can result in lower bioavailability, higher bound fraction and lower urinary excretion, which would hamper later development processes and might result in considerable drug-drug interaction. The criteria should be adjusted according to the pharmacological profiles of the agents in question and depending on the estimated profit, but ignoring these criteria may result in a significant waste of time and money during drug development.

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“…Derivatives of this compound bind not only to BZD receptors of the central nervous system, but also to cholecystokinin receptors [21,23]. Moreover, BZD compounds also act as Ras farnesyltransferase Table 1 / and Y angles (degree) of residues i+1 and i+2 and C aI -C ai+1 -C ai+2 -C ai+3 angles (degree) in the representative experimental b-turns and ideal b-turns used in this study a C aI -C ai+1 -C ai+2 -C ai+3 angle of the peptide b Structure B of 5CHA c Type VIa1 inhibitors, HIV tat antagonists, reverse transcriptase inhibitors, j-selective opioid antagonists, platelet activation factor antagonists or glycoprotein IIb/IIIa inhibitors [24,25]. BZDs may demonstrate such widespread biological activities because the BZD central ring structure is a priviledged structure that can orient substituents to mimic the side-chain orientations of peptide reverse-turn structures, a common recognition motif in biological systems.…”

Section: Introductionmentioning

confidence: 99%

Do benzodiazepines mimic reverse-turn structures?

Hata

Marshall

2006

J Comput Aided Mol Des

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The role of benzodiazepine derivatives (BZD) as a privileged scaffold that mimics beta-turn structures (Ripka et al. (1993) Tetrahedron 49:3593-3608) in peptide/protein recognition was reexamined in detail. Stable BZD ring conformers were determined with MM3, and experimental reverse-turn structures were extracted from the basis set of protein crystal structures previously defined by Ripka et al. Ideal beta-turns were also modeled and similarly compared with BZD conformers. Huge numbers of conformers were generated by systematically scanning the torsional degrees of freedom for BZDs, as well as those of ideal beta-turns for comparison. Using these structures, conformers of BZDs were fit to experimental structures as suggested by Ripka et al., or modeled classical beta-turn conformers, and the root-mean-square deviation (RMSD) values were calculated for each pairwise comparison. Pairs of conformers with the smallest RMSD values for overlap of the four alpha-beta side-chain orientations were selected. All overlaps of BZD conformers with experimental beta-turns yielded one or more comparisons where the least RMSD was significantly small, 0.48-0.86 angstroms, as previously suggested. Utilizing a different methodology, the overall conclusion that benzodiazepines could serve as reverse-turn mimetics of Ripka et al. is justified. The least RMSD values for the overlap of BZDs and modeled classical beta-turns were also less than 1 angstrom. When comparing BZDs with experimental or classical beta-turns, the set of experimental beta-turns selected by Ripka et al. fit the BZD scaffolds better than modeled classical beta-turns; however, all the experimental beta-turns did not fit a particular BZD scaffold better. A single BZD ring conformation, and/or chiral orientation, can mimic some, but not all, of the experimental beta-turn structures. BZD has two central ring conformations and one chiral center that explains why the four variations of the BZD scaffold can mimic all types of beta-turn structure examined. It was found, moreover, that the BZD scaffold also mimics each of the nine clusters of experimental orientations of side chains of reverse turns in the Protein Data Bank, when the new classification scheme for the four side-chain directions (the relative orientations of alpha-beta vectors of residues i through i+3) was considered (Tran et al. (2005) J Comput-Aided Mol Des 19:551-566).

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The search for orally active medications through combinatorial chemistry

Cited by 75 publications

References 97 publications

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

Molecular and Pharmacokinetic Properties of 222 Commercially Available Oral Drugs in Humans.

Do benzodiazepines mimic reverse-turn structures?

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