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Identification of potential inhibitors based on compound proposal contest: Tyrosine-protein kinase Yes as a target.

Chiba S, Ikeda K, Ishida T, Gromiha MM, Taguchi YH, Iwadate M, Umeyama H, Hsin KY, Kitano H, Yamamoto K, Sugaya N, Kato K, Okuno T, Chikenji G, Mochizuki M, Yasuo N, Yoshino R, Yanagisawa K, Ban T, Teramoto R, Ramakrishnan C, Thangakani AM, Velmurugan D, Prathipati P, Ito J, Tsuchiya Y, Mizuguchi K, Honma T, Hirokawa T, Akiyama Y, Sekijima M - Sci Rep (2015)

Bottom Line: A search of broader range of chemical space is important for drug discovery.We held a compound proposal contest, in which multiple research groups participated and predicted inhibitors of tyrosine-protein kinase Yes.This showed whether collective knowledge based on individual approaches helped to obtain hit compounds from a broad range of chemical space and whether the contest-based approach was effective.

View Article: PubMed Central - PubMed

Affiliation: Education Academy of Computational Life Sciences (ACLS), Tokyo Institute of Technology, 4259 Nagatsutacho, Midori-ku, Yokohama 226-8501 Japan.

ABSTRACT
A search of broader range of chemical space is important for drug discovery. Different methods of computer-aided drug discovery (CADD) are known to propose compounds in different chemical spaces as hit molecules for the same target protein. This study aimed at using multiple CADD methods through open innovation to achieve a level of hit molecule diversity that is not achievable with any particular single method. We held a compound proposal contest, in which multiple research groups participated and predicted inhibitors of tyrosine-protein kinase Yes. This showed whether collective knowledge based on individual approaches helped to obtain hit compounds from a broad range of chemical space and whether the contest-based approach was effective.

No MeSH data available.


Related in: MedlinePlus

Distribution of compound properties for Enamine library, submitted compounds, and Src family kinase inhibitors.
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f2: Distribution of compound properties for Enamine library, submitted compounds, and Src family kinase inhibitors.

Mentions: We analyzed the characteristic features of the 1200 submitted compounds (1180 unique compound structures) using their chemical properties: molecular weight (MW), ALogP, number of hydrogen bond acceptors (HBA), number of hydrogen bond donors (HBD), number of aromatic rings (AROM), and number of rotatable bonds (ROTB) using Canvas Version 2.2.01361. In addition, we analyzed the structures of 3528 known Src family kinase inhibitors retrieved from ChEMBL and BindingDB and the randomly selected 211546 structures from the Enamine library for comparison. Figure 2 shows the distribution of the six chemical properties for these three sets of compounds. We observed that for four of the six considered properties, there was a marked difference between the average values of the submitted compounds (AlogP: 3.2, HBA: 3.6, HBD: 1.4, AROM: 3.6) and the Enamine library compounds (AlogP: 2.1, HBA: 3.1, HBD: 1.0, AROM: 2.6), and the properties were biased toward the average values of Src family kinase inhibitors (AlogP: 3.8, HBA: 4.5, HBD: 2.3, AROM: 4.0). Notably, the average ROTB value of the submitted compounds (ROTB: 4.7) was smaller than that of the Enamine library (ROTB: 5.5), which is closer to the average ROTB value of the Src family kinase inhibitors (ROTB: 6.4), although the average ROTB value of the potential hit compounds was 5.7. In addition, the average MW of submitted compounds (MW: 361) was similar to that of the Enamine library (MW: 365), although the average MW of the potential hit compounds was 391, which is closer to the MW of the Src family kinase inhibitors (MW: 455). This analysis suggests that the prediction methods could be improved by considering ROTB and MW. In particular, for docking simulation, special consideration would be necessary when known inhibitors have a large ROTB value, because it is more difficult to cover the conformational space of compounds.


Identification of potential inhibitors based on compound proposal contest: Tyrosine-protein kinase Yes as a target.

Chiba S, Ikeda K, Ishida T, Gromiha MM, Taguchi YH, Iwadate M, Umeyama H, Hsin KY, Kitano H, Yamamoto K, Sugaya N, Kato K, Okuno T, Chikenji G, Mochizuki M, Yasuo N, Yoshino R, Yanagisawa K, Ban T, Teramoto R, Ramakrishnan C, Thangakani AM, Velmurugan D, Prathipati P, Ito J, Tsuchiya Y, Mizuguchi K, Honma T, Hirokawa T, Akiyama Y, Sekijima M - Sci Rep (2015)

Distribution of compound properties for Enamine library, submitted compounds, and Src family kinase inhibitors.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4660442&req=5

f2: Distribution of compound properties for Enamine library, submitted compounds, and Src family kinase inhibitors.
Mentions: We analyzed the characteristic features of the 1200 submitted compounds (1180 unique compound structures) using their chemical properties: molecular weight (MW), ALogP, number of hydrogen bond acceptors (HBA), number of hydrogen bond donors (HBD), number of aromatic rings (AROM), and number of rotatable bonds (ROTB) using Canvas Version 2.2.01361. In addition, we analyzed the structures of 3528 known Src family kinase inhibitors retrieved from ChEMBL and BindingDB and the randomly selected 211546 structures from the Enamine library for comparison. Figure 2 shows the distribution of the six chemical properties for these three sets of compounds. We observed that for four of the six considered properties, there was a marked difference between the average values of the submitted compounds (AlogP: 3.2, HBA: 3.6, HBD: 1.4, AROM: 3.6) and the Enamine library compounds (AlogP: 2.1, HBA: 3.1, HBD: 1.0, AROM: 2.6), and the properties were biased toward the average values of Src family kinase inhibitors (AlogP: 3.8, HBA: 4.5, HBD: 2.3, AROM: 4.0). Notably, the average ROTB value of the submitted compounds (ROTB: 4.7) was smaller than that of the Enamine library (ROTB: 5.5), which is closer to the average ROTB value of the Src family kinase inhibitors (ROTB: 6.4), although the average ROTB value of the potential hit compounds was 5.7. In addition, the average MW of submitted compounds (MW: 361) was similar to that of the Enamine library (MW: 365), although the average MW of the potential hit compounds was 391, which is closer to the MW of the Src family kinase inhibitors (MW: 455). This analysis suggests that the prediction methods could be improved by considering ROTB and MW. In particular, for docking simulation, special consideration would be necessary when known inhibitors have a large ROTB value, because it is more difficult to cover the conformational space of compounds.

Bottom Line: A search of broader range of chemical space is important for drug discovery.We held a compound proposal contest, in which multiple research groups participated and predicted inhibitors of tyrosine-protein kinase Yes.This showed whether collective knowledge based on individual approaches helped to obtain hit compounds from a broad range of chemical space and whether the contest-based approach was effective.

View Article: PubMed Central - PubMed

Affiliation: Education Academy of Computational Life Sciences (ACLS), Tokyo Institute of Technology, 4259 Nagatsutacho, Midori-ku, Yokohama 226-8501 Japan.

ABSTRACT
A search of broader range of chemical space is important for drug discovery. Different methods of computer-aided drug discovery (CADD) are known to propose compounds in different chemical spaces as hit molecules for the same target protein. This study aimed at using multiple CADD methods through open innovation to achieve a level of hit molecule diversity that is not achievable with any particular single method. We held a compound proposal contest, in which multiple research groups participated and predicted inhibitors of tyrosine-protein kinase Yes. This showed whether collective knowledge based on individual approaches helped to obtain hit compounds from a broad range of chemical space and whether the contest-based approach was effective.

No MeSH data available.


Related in: MedlinePlus