publication . Article . Other literature type . 2017

Genomes, structural biology and drug discovery: combating the impacts of mutations in genetic disease and antibiotic resistance

Pandurangan, AP; Ascher, David; Thomas, Sherine; Blundell, Tom;
Open Access English
  • Published: 23 Mar 2017 Journal: Biochemical Society Transactions, volume 45, issue 2, pages 303-311 (issn: 0300-5127, eissn: 1470-8752, Copyright policy)
  • Publisher: Portland Press Ltd.
  • Country: United Kingdom
Abstract
For over four decades structural biology has been used to understand the mechanisms of disease, and structure-guided approaches have demonstrated clearly that they can contribute to many aspects of early drug discovery, both computationally and experimentally. Structure can also inform our understanding of impacts of mutations in human genetic diseases and drug resistance in cancers and infectious diseases. We discuss the ways that structural insights might be useful in both repurposing off-licence drugs and guide the design of new molecules that might be less susceptible to drug resistance in the future. D.B.A. and T.L.B. are supported by the Wellcome Trust Pro...
Subjects
free text keywords: Review Articles, Review Article, 4, 17, 48, antimicrobial resistance, genetic disease, mutational analysis, structure-guided drug discovery, Biochemistry, Drug discovery, Disease, Drug repositioning, Antibiotic resistance, Repurposing, Genetics, Structural biology, Mutation, medicine.disease_cause, medicine, Drug resistance, Biology
Funded by
WT| Structural Biology of DNA Repair: Spatial Organisation of the Multicomponent Complexes of Non-Homologous End Joining.
Project
  • Funder: Wellcome Trust (WT)
  • Project Code: 093167
  • Funding stream: Cellular and Molecular Neuroscience
,
EC| MM4TB
Project
MM4TB
More Medicines for Tuberculosis
  • Funder: European Commission (EC)
  • Project Code: 260872
  • Funding stream: FP7 | SP1 | HEALTH
61 references, page 1 of 5

1 Perutz R.R., Liquori A.M. and Eirich F (1951) X-ray and solubility studies of the haemoglobin of sickle-cell anaemia patients. Nature 167, 929–931 PMID:14843112 [PubMed]

2 Perutz M.F., Rossmann M.G., Cullis A.F., Muirhead H., Will G. and North A.C.T. (1960) Structure of hæmoglobin: a three-dimensional Fourier synthesis at 5.5-Å. Resolution, obtained by X-ray analysis. Nature 185, 416–422 doi:10.1038/185416a0 18990801 [OpenAIRE] [PubMed] [DOI]

3 Phillips D.C. (1966) The three-dimensional structure of an enzyme molecule. Sci. Am. 215, 78–90 doi:10.1038/scientificamerican1166-78 [OpenAIRE] [DOI]

4 Adams M.J., Blundell T.L., Dodson E.J., Dodson G.G., Vijayan M., Baker E.N.et al. (1969) Structure of rhombohedral 2 zinc insulin crystals. Nature 224, 491–495 doi:10.1038/224491a0 [OpenAIRE] [DOI]

5 Pullen R.A., Lindsay D.G., Wood S.P., Tickle I.J., Blundell T.L., Wollmer A.et al. (1976) Receptor-binding region of insulin. Nature 259, 369–373 doi:10.1038/259369a0 175286 [OpenAIRE] [PubMed] [DOI]

6 Browne W.J., North A.C.T., Phillips D.C., Brew K., Vanaman T.C. and Hill R.L. (1969) A possible three-dimensional structure of bovine α-lactalbumin based on that of hen's egg-white lysozyme. J. Mol. Biol. 42, 65–86 doi:10.1016/0022-2836(69)90487-2 5817651 [OpenAIRE] [PubMed] [DOI]

7 Bedarkar S., Turnell W.G., Blundell T.L. and Schwabe C (1977) Relaxin has conformational homology with insulin. Nature 270, 449–451 doi:10.1038/2 70449a0 593365 [PubMed] [DOI]

8 Blundell T.L., Bedarkar S., Rinderknecht E. and Humbel R.E. (1978) Insulin-like growth factor: a model for tertiary structure accounting for immunoreactivity and receptor binding. Proc. Natl Acad. Sci. U.S.A. 75, 180–184 doi:10.1073/pnas.75.1.180 272633 [OpenAIRE] [PubMed] [DOI]

9 Fyhrquist F. and Saijonmaa O (2008) Renin-angiotensin system revisited. J. Intern. Med. 264, 224–236 doi:10.1111/j.1365-2796.2008.01981.x 18793332 [OpenAIRE] [PubMed] [DOI]

10 Blundell T., Sibanda B.L. and Pearl L (1983) Three-dimensional structure, specificity and catalytic mechanism of renin. Nature 304, 273–275 doi:10.1038/304273a0 6346109 [OpenAIRE] [PubMed] [DOI]

11 Foundling S.I., Cooper J., Watson F.E., Cleasby A., Pearl L.H., Sibanda B.L.et al. (1987) High resolution X-ray analyses of renin inhibitor-aspartic proteinase complexes. Nature 327, 349–352 doi:10.1038/327349a0 3295561 [OpenAIRE] [PubMed] [DOI]

12 Rahuel J., Priestle J.P. and Grütter M.G. (1991) The crystal structures of recombinant glycosylated human renin alone and in complex with a transition state analog inhibitor. J. Struct. Biol. 107, 227–236 doi:10.1016/1047-8477(91)90048-2 1807356 [OpenAIRE] [PubMed] [DOI]

13 Dhanaraj V., Dealwis C.G., Frazao C., Badasso M., Sibanda B.L., Tickle I.J.et al. (1992) X-ray analyses of peptide–inhibitor complexes define the structural basis of specificity for human and mouse renins. Nature 357, 466–472 doi:10.1038/357466a0 1608447 [OpenAIRE] [PubMed] [DOI]

14 Abagyan R. and Totrov M (2001) High-throughput docking for lead generation. Curr. Opin. Chem. Biol. 5, 375–382 doi:10.1016/S1367-5931(00)00217-9 11470599 [OpenAIRE] [PubMed] [DOI]

15 Albiston A.L., Morton C.J., Ng H.L., Pham V., Yeatman H.R., Ye S.et al. (2008) Identification and characterization of a new cognitive enhancer based on inhibition of insulin-regulated aminopeptidase. FASEB J. 22, 4209–4217 doi:10.1096/fj.08-112227 18716029 [OpenAIRE] [PubMed] [DOI]

61 references, page 1 of 5
Abstract
For over four decades structural biology has been used to understand the mechanisms of disease, and structure-guided approaches have demonstrated clearly that they can contribute to many aspects of early drug discovery, both computationally and experimentally. Structure can also inform our understanding of impacts of mutations in human genetic diseases and drug resistance in cancers and infectious diseases. We discuss the ways that structural insights might be useful in both repurposing off-licence drugs and guide the design of new molecules that might be less susceptible to drug resistance in the future. D.B.A. and T.L.B. are supported by the Wellcome Trust Pro...
Subjects
free text keywords: Review Articles, Review Article, 4, 17, 48, antimicrobial resistance, genetic disease, mutational analysis, structure-guided drug discovery, Biochemistry, Drug discovery, Disease, Drug repositioning, Antibiotic resistance, Repurposing, Genetics, Structural biology, Mutation, medicine.disease_cause, medicine, Drug resistance, Biology
Funded by
WT| Structural Biology of DNA Repair: Spatial Organisation of the Multicomponent Complexes of Non-Homologous End Joining.
Project
  • Funder: Wellcome Trust (WT)
  • Project Code: 093167
  • Funding stream: Cellular and Molecular Neuroscience
,
EC| MM4TB
Project
MM4TB
More Medicines for Tuberculosis
  • Funder: European Commission (EC)
  • Project Code: 260872
  • Funding stream: FP7 | SP1 | HEALTH
61 references, page 1 of 5

1 Perutz R.R., Liquori A.M. and Eirich F (1951) X-ray and solubility studies of the haemoglobin of sickle-cell anaemia patients. Nature 167, 929–931 PMID:14843112 [PubMed]

2 Perutz M.F., Rossmann M.G., Cullis A.F., Muirhead H., Will G. and North A.C.T. (1960) Structure of hæmoglobin: a three-dimensional Fourier synthesis at 5.5-Å. Resolution, obtained by X-ray analysis. Nature 185, 416–422 doi:10.1038/185416a0 18990801 [OpenAIRE] [PubMed] [DOI]

3 Phillips D.C. (1966) The three-dimensional structure of an enzyme molecule. Sci. Am. 215, 78–90 doi:10.1038/scientificamerican1166-78 [OpenAIRE] [DOI]

4 Adams M.J., Blundell T.L., Dodson E.J., Dodson G.G., Vijayan M., Baker E.N.et al. (1969) Structure of rhombohedral 2 zinc insulin crystals. Nature 224, 491–495 doi:10.1038/224491a0 [OpenAIRE] [DOI]

5 Pullen R.A., Lindsay D.G., Wood S.P., Tickle I.J., Blundell T.L., Wollmer A.et al. (1976) Receptor-binding region of insulin. Nature 259, 369–373 doi:10.1038/259369a0 175286 [OpenAIRE] [PubMed] [DOI]

6 Browne W.J., North A.C.T., Phillips D.C., Brew K., Vanaman T.C. and Hill R.L. (1969) A possible three-dimensional structure of bovine α-lactalbumin based on that of hen's egg-white lysozyme. J. Mol. Biol. 42, 65–86 doi:10.1016/0022-2836(69)90487-2 5817651 [OpenAIRE] [PubMed] [DOI]

7 Bedarkar S., Turnell W.G., Blundell T.L. and Schwabe C (1977) Relaxin has conformational homology with insulin. Nature 270, 449–451 doi:10.1038/2 70449a0 593365 [PubMed] [DOI]

8 Blundell T.L., Bedarkar S., Rinderknecht E. and Humbel R.E. (1978) Insulin-like growth factor: a model for tertiary structure accounting for immunoreactivity and receptor binding. Proc. Natl Acad. Sci. U.S.A. 75, 180–184 doi:10.1073/pnas.75.1.180 272633 [OpenAIRE] [PubMed] [DOI]

9 Fyhrquist F. and Saijonmaa O (2008) Renin-angiotensin system revisited. J. Intern. Med. 264, 224–236 doi:10.1111/j.1365-2796.2008.01981.x 18793332 [OpenAIRE] [PubMed] [DOI]

10 Blundell T., Sibanda B.L. and Pearl L (1983) Three-dimensional structure, specificity and catalytic mechanism of renin. Nature 304, 273–275 doi:10.1038/304273a0 6346109 [OpenAIRE] [PubMed] [DOI]

11 Foundling S.I., Cooper J., Watson F.E., Cleasby A., Pearl L.H., Sibanda B.L.et al. (1987) High resolution X-ray analyses of renin inhibitor-aspartic proteinase complexes. Nature 327, 349–352 doi:10.1038/327349a0 3295561 [OpenAIRE] [PubMed] [DOI]

12 Rahuel J., Priestle J.P. and Grütter M.G. (1991) The crystal structures of recombinant glycosylated human renin alone and in complex with a transition state analog inhibitor. J. Struct. Biol. 107, 227–236 doi:10.1016/1047-8477(91)90048-2 1807356 [OpenAIRE] [PubMed] [DOI]

13 Dhanaraj V., Dealwis C.G., Frazao C., Badasso M., Sibanda B.L., Tickle I.J.et al. (1992) X-ray analyses of peptide–inhibitor complexes define the structural basis of specificity for human and mouse renins. Nature 357, 466–472 doi:10.1038/357466a0 1608447 [OpenAIRE] [PubMed] [DOI]

14 Abagyan R. and Totrov M (2001) High-throughput docking for lead generation. Curr. Opin. Chem. Biol. 5, 375–382 doi:10.1016/S1367-5931(00)00217-9 11470599 [OpenAIRE] [PubMed] [DOI]

15 Albiston A.L., Morton C.J., Ng H.L., Pham V., Yeatman H.R., Ye S.et al. (2008) Identification and characterization of a new cognitive enhancer based on inhibition of insulin-regulated aminopeptidase. FASEB J. 22, 4209–4217 doi:10.1096/fj.08-112227 18716029 [OpenAIRE] [PubMed] [DOI]

61 references, page 1 of 5
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