Site Identification and Next Choice Protocol for Hit-to-Lead Optimization
Time efficiency and cost savings are major challenges in drug discovery and development. In this process, the hit-to-lead stage is expected to improve efficiency because it primarily exploits the trial-and-error approach of medicinal chemists. This study proposes a site identification and next choic...
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| Published in | Journal of Chemical Information and Modeling Vol. 64; no. 11; pp. 4475 - 4484 |
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| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Chemical Society
10.06.2024
American Chemical Society (ACS) |
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| Abstract | Time efficiency and cost savings are major challenges in drug discovery and development. In this process, the hit-to-lead stage is expected to improve efficiency because it primarily exploits the trial-and-error approach of medicinal chemists. This study proposes a site identification and next choice (SINCHO) protocol to improve the hit-to-lead efficiency. This protocol selects an anchor atom and growth site pair, which is desirable for a hit-to-lead strategy starting from a 3D complex structure. We developed and fine-tuned the protocol using a training data set and assessed it using a test data set of the preceding hit-to-lead strategy. The protocol was tested for experimentally determined structures and molecular dynamics (MD) ensembles. The protocol had a high prediction accuracy for applying MD ensembles, owing to the consideration of protein flexibility. The SINCHO protocol enables medicinal chemists to visualize and modify functional groups in a hit-to-lead manner. |
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| AbstractList | Time efficiency and cost savings are major challenges
in drug discovery
and development. In this process, the hit-to-lead stage is expected
to improve efficiency because it primarily exploits the trial-and-error
approach of medicinal chemists. This study proposes a site identification
and next choice (SINCHO) protocol to improve the hit-to-lead efficiency.
This protocol selects an anchor atom and growth site pair, which is
desirable for a hit-to-lead strategy starting from a 3D complex structure.
We developed and fine-tuned the protocol using a training data set
and assessed it using a test data set of the preceding hit-to-lead
strategy. The protocol was tested for experimentally determined structures
and molecular dynamics (MD) ensembles. The protocol had a high prediction
accuracy for applying MD ensembles, owing to the consideration of
protein flexibility. The SINCHO protocol enables medicinal chemists
to visualize and modify functional groups in a hit-to-lead manner. Time efficiency and cost savings are major challenges in drug discovery and development. In this process, the hit-to-lead stage is expected to improve efficiency because it primarily exploits the trial-and-error approach of medicinal chemists. This study proposes a site identification and next choice (SINCHO) protocol to improve the hit-to-lead efficiency. This protocol selects an anchor atom and growth site pair, which is desirable for a hit-to-lead strategy starting from a 3D complex structure. We developed and fine-tuned the protocol using a training data set and assessed it using a test data set of the preceding hit-to-lead strategy. The protocol was tested for experimentally determined structures and molecular dynamics (MD) ensembles. The protocol had a high prediction accuracy for applying MD ensembles, owing to the consideration of protein flexibility. The SINCHO protocol enables medicinal chemists to visualize and modify functional groups in a hit-to-lead manner. Time efficiency and cost savings are major challenges in drug discovery and development. In this process, the hit-to-lead stage is expected to improve efficiency because it primarily exploits the trial-and-error approach of medicinal chemists. This study proposes a site identification and next choice (SINCHO) protocol to improve the hit-to-lead efficiency. This protocol selects an anchor atom and growth site pair, which is desirable for a hit-to-lead strategy starting from a 3D complex structure. We developed and fine-tuned the protocol using a training data set and assessed it using a test data set of the preceding hit-to-lead strategy. The protocol was tested for experimentally determined structures and molecular dynamics (MD) ensembles. The protocol had a high prediction accuracy for applying MD ensembles, owing to the consideration of protein flexibility. The SINCHO protocol enables medicinal chemists to visualize and modify functional groups in a hit-to-lead manner.Time efficiency and cost savings are major challenges in drug discovery and development. In this process, the hit-to-lead stage is expected to improve efficiency because it primarily exploits the trial-and-error approach of medicinal chemists. This study proposes a site identification and next choice (SINCHO) protocol to improve the hit-to-lead efficiency. This protocol selects an anchor atom and growth site pair, which is desirable for a hit-to-lead strategy starting from a 3D complex structure. We developed and fine-tuned the protocol using a training data set and assessed it using a test data set of the preceding hit-to-lead strategy. The protocol was tested for experimentally determined structures and molecular dynamics (MD) ensembles. The protocol had a high prediction accuracy for applying MD ensembles, owing to the consideration of protein flexibility. The SINCHO protocol enables medicinal chemists to visualize and modify functional groups in a hit-to-lead manner. |
| Author | Kudo, Genki Yoshino, Ryunosuke Hirokawa, Takatsugu Hirao, Takumi Shigeta, Yasuteru |
| AuthorAffiliation | University of Tsukuba Division of Biomedical Science, Faculty of Medicine Physics Department, Graduate School of Pure and Applied Sciences Transborder Medical Research Center Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences Center for Computational Sciences |
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| Author_xml | – sequence: 1 givenname: Genki orcidid: 0000-0002-4727-7002 surname: Kudo fullname: Kudo, Genki organization: Physics Department, Graduate School of Pure and Applied Sciences – sequence: 2 givenname: Takumi surname: Hirao fullname: Hirao, Takumi organization: University of Tsukuba – sequence: 3 givenname: Ryunosuke surname: Yoshino fullname: Yoshino, Ryunosuke organization: University of Tsukuba – sequence: 4 givenname: Yasuteru orcidid: 0000-0002-3219-6007 surname: Shigeta fullname: Shigeta, Yasuteru organization: University of Tsukuba – sequence: 5 givenname: Takatsugu orcidid: 0000-0002-3180-5050 surname: Hirokawa fullname: Hirokawa, Takatsugu email: t-hirokawa@md.tsukuba.ac.jp organization: University of Tsukuba |
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| Snippet | Time efficiency and cost savings are major challenges in drug discovery and development. In this process, the hit-to-lead stage is expected to improve... Time efficiency and cost savings are major challenges in drug discovery and development. In this process, the hit-to-lead stage is expected to improve... |
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| SubjectTerms | Chemists Computational Biochemistry Datasets Drug Design Drug Discovery - methods Efficiency Error analysis Functional groups Molecular dynamics Molecular Dynamics Simulation Protein Conformation Proteins - chemistry |
| Title | Site Identification and Next Choice Protocol for Hit-to-Lead Optimization |
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