A new approach to analysis and display of local lipophilicity/hydrophilicity mapped on molecular surfaces

Heiden, Wolfgang; Moeckel, Gerd; Brickmann, Jürgen

doi:10.1007/bf00124359

Cited by 181 publications

(147 citation statements)

References 20 publications

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“…The molecular Connolly (7) and MOLCAD (20) surfaces were generated, and the lipophilic and hydrogen-bonding properties were displayed using an opaque coloring style.…”

Section: Patientsmentioning

confidence: 99%

Impact of Y143 HIV-1 Integrase Mutations on Resistance to Raltegravir In Vitro and In Vivo

Delelis

Thierry

Subra

et al. 2010

Antimicrob Agents Chemother

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Integrase (IN), the HIV-1 enzyme responsible for the integration of the viral genome into the chromosomes of infected cells, is the target of the recently approved antiviral raltegravir (RAL). Despite this drug's activity against viruses resistant to other antiretrovirals, failures of raltegravir therapy were observed, in association with the emergence of resistance due to mutations in the integrase coding region. Two pathways involving primary mutations on residues N155 and Q148 have been characterized. It was suggested that mutations at residue Y143 might constitute a third primary pathway for resistance. The aims of this study were to investigate the susceptibility of HIV-1 Y143R/C mutants to raltegravir and to determine the effects of these mutations on the IN-mediated reactions. Our observations demonstrate that Y143R/C mutants are strongly impaired for both of these activities in vitro. However, Y143R/C activity can be kinetically restored, thereby reproducing the effect of the secondary G140S mutation that rescues the defect associated with the Q148R/H mutants. A molecular modeling study confirmed that Y143R/C mutations play a role similar to that determined for Q148R/H mutations. In the viral replicative context, this defect leads to a partial block of integration responsible for a weak replicative capacity. Nevertheless, the Y143 mutant presented a high level of resistance to raltegravir. Furthermore, the 50% effective concentration (EC 50 ) determined for Y143R/C mutants was significantly higher than that obtained with G140S/Q148R mutants. Altogether our results not only show that the mutation at position Y143 is one of the mechanisms conferring resistance to RAL but also explain the delayed emergence of this mutation.

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“…The molecular Connolly (7) and MOLCAD (20) surfaces were generated, and the lipophilic and hydrogen-bonding properties were displayed using an opaque coloring style.…”

Section: Patientsmentioning

confidence: 99%

Impact of Y143 HIV-1 Integrase Mutations on Resistance to Raltegravir In Vitro and In Vivo

Delelis

Thierry

Subra

et al. 2010

Antimicrob Agents Chemother

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“…The ATP molecule is shown by the ball-andstick representation. The molecular surface of these residues (calculated by the molecular surface (MS) program 114 ) is shown in Figure 3B . Residues 51E, 80F, 81E, 83L, 84H, 85Q, 86D, 89K, 131N, 137T, and 145D form a sort of " ring " (carbon atoms for these residues are colored cyan) around the ATP molecule, whereas residues 33K and 10I (carbon atoms for these residues are colored gray) interact with the ATP molecule perpendicular to the ring.…”

Section: Adenosine Triphosphate Binding Pocket In Cyclin-dependent Kimentioning

confidence: 99%

Selectivity and potency of cyclin-dependent kinase inhibitors

Sridhar

Akula

Pattabiraman

2006

AAPS J

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A BSTRACTMembers of the cyclin-dependent kinase (CDK) family play key roles in various cellular processes. There are 11 members of the CDK family known till now. CDKs are activated by forming noncovalent complexes with cyclins such as A-, B-, C-, D-(D1, D2, and D3), and E-type cyclins. Each isozyme of this family is responsible for particular aspects (cell signaling, transcription, etc) of the cell cycle, and some of the CDK isozymes are specifi c to certain kinds of tissues. Aberrant expression and overexpression of these kinases are evidenced in many disease conditions. Inhibition of isozymes of CDKs specifi cally can yield benefi ciary treatment modalities with minimum side effects. More than 80 3-dimensional structures of CDK2, CDK5, and CDK6 complexed with inhibitors have been published. This review provides an understanding of the structural aspects of CDK isozymes and binding modes of various known CDK inhibitors so that these kinases can be better targeted for drug discovery and design. The amino acid residues that constitute the cyclin binding region, the substrate binding region, and the area around the adenosine triphosphate (ATP) binding site have been compared for CDK isozymes. Those amino acids at the ATP binding site that could be used to improve the potency and subtype specifi city have been described.

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“…They were frequently used as molecular descriptors by themselves [3,6,8] or as a starting point for deriving other parameters, e.g. lipophilicity/ hydrophilicity [9], surface tension parameters [10], Weighted Holistic Invariant Molecular (WHIM) descriptors [11] and so on.…”

Section: Introductionmentioning

confidence: 99%

Molecular van der Waals Space and Topological Indices from the Distance Matrix

Ciubotariu¹,

Medeleanu

Vlaia³

et al. 2004

Molecules

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A comparative study of 36 molecular descriptors derived from the topological distance matrix and van der Waals space is carried out within this paper. They are partitioned into 16 generalized topological distance matrix indices, 11 topological distance indices known in the literature (seven obtained from eigenvalues/eigenvectors of distance matrix), and 9 van der Waals molecular descriptors. The generalized topological distance indices, k δ λ (λ = 1 -3, k = 1 -4), are introduced in this work on the basis of reciprocical distance matrix. Intercorrelation analysis reveals that topological distance indices mostly contain the same type of information, while van der Waals indices can be bound to the shape or the size of molecules. Furthermore, we found that topological distance indices are good for describing molecular size, and they may be viewed as bulk parameters. The most accurate QSPR models for predicting boiling point of alkanes are based on some of the generalized, eigenvalues/eigenvectors topological distance indices and the van der Waals descriptors of molecular size.

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A new approach to analysis and display of local lipophilicity/hydrophilicity mapped on molecular surfaces

Cited by 181 publications

References 20 publications

Impact of Y143 HIV-1 Integrase Mutations on Resistance to Raltegravir In Vitro and In Vivo

Impact of Y143 HIV-1 Integrase Mutations on Resistance to Raltegravir In Vitro and In Vivo

Selectivity and potency of cyclin-dependent kinase inhibitors

Molecular van der Waals Space and Topological Indices from the Distance Matrix

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