Fast, accurate, and practical binding site identification

The Importance of Understanding Protein Sites

Understanding the structure and exploiting the function of protein active sites is a cornerstone of drug design. Doing so requires chemists to know the location of these sites, yet at the outset of many drug design projects the location of a binding site for protein-ligand or protein-protein interactions remains unknown. Additionally, it is equally important to identify the locations of any potential allosteric binding sites.

SiteMap's proven algorithm for binding site identification and evaluation can help researchers to locate binding sites with a high degree of confidence and predict the druggability of those sites. Beyond lead discovery, SiteMap assists in lead optimization by providing insight into ligand-receptor interactions so as to suggest effective strategies to modify lead compounds to enhance receptor complementarity.

Rapid site identification and ranking:
SiteMap can treat entire proteins to locate binding sites whose size, functionality, and extent of solvent exposure meet user specifications. SiteScore, the scoring function used to assess a site's propensity for ligand binding, accurately ranks possible binding sites to eliminate those not likely to be pharmaceutically relevant.

Integration with Glide:
SiteMap fits perfectly into the Schrödinger structure-based drug design work flow. Sites identified by SiteMap can easily be used to set up Glide grids for virtual screening experiments.

Site visualization tools:
SiteMap highlights regions within the binding site suitable for occupancy by hydrophobic groups or by ligand hydrogen-bond donors, acceptors, or metal-binding functionality. Distinguishing the different binding site sub-regions allows for ready assessment of a ligand's complementarity.

Tools for exploiting targets of opportunity:
Active site maps show where modifications to a ligand structure would be expected to promote binding.

Citations and Acknowledgements

Schrödinger Release 2021-4: SiteMap, Schrödinger, LLC, New York, NY, 2021.

Halgren, T., "Identifying and Characterizing Binding Sites and Assessing Druggability," J. Chem. Inf. Model., 2009, 49, 377–389.

Halgren, T., "New Method for Fast and Accurate Binding-site Identification and Analysis," Chem. Biol. Drug Des., 2007, 69, 146–148.

"Toward in vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia"

Wan, H.; Selvaggio, G.; Pearlstein, R.A., BioRxiv, 2020, Preprint, XXX-XXX

ö "Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia"

Minuesa, G.; Albanese, S. K.; Xie, W.; Kazansky, Y.; Worroll, D. et al., Nature Communications, 2019, 10, 2691 (2019)

ö "Mechanistic and Computational Studies of the Reductive Half-Reaction of Tyrosine to Phenylalanine Active Site Variants of d-Arginine Dehydrogenase"

Gannavaram, S.; Sirin, S.; Sherman, W.; Gadda, G., Biochemistry, 2014, 53(41), 6574-6583

ö "A Computational Approach to Enzyme Design: Predicting ω-Aminotransferase Catalytic Activity Using Docking and MM-GBSA Scoring"

Sirin, S.; Kumar, R.; Martinez, C.; Karmilowicz, M.J.; Ghosh, P.; Abramov, Y.A.; Martin, V.; Sherman, W., J. Chem. Inf. Model., 2014, 54(8), 2334-2346

ö "Improved docking of polypeptides with Glide"

Tubert-Brohman, I.; Sherman, W.; Repasky, M.; Beuming, T., J. Chem. Inf. Model., 2013, 53(7), 1689-1699

ö "Identifying and characterizing binding sites and assessing druggability"

Halgren, T., J. Chem. Inf. Model., 2009, 49, 377–389

"Driving forces for ligand migration in the leucine transporter"

Jorgensen, A. M.; Topiol, S., Chem. Biol. Drug Des, 2008, 72, 265-272

ö "New method for fast and accurate binding-site identification and analysis"

Halgren, T., Chem. Biol. Drug Des., 2007, 69, 146–148
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