Time filter

Source Type

New Haven, CT, United States

Audie J.,CMD Bioscience | Audie J.,Sacred Heart University at Connecticut | Swanson J.,ChemModeling LLC
Chemical Biology and Drug Design

Peptides hold great promise as novel medicinal and biologic agents, and computational methods can help unlock that promise. In particular, structure-based peptide design can be used to identify and optimize peptide ligands. Successful structure-based design, in turn, requires accurate and fast methods for predicting protein-peptide binding affinities. Here, we review the development of such methods, emphasizing structure-based methods that assume rigid-body association and the single-structure approximation. We also briefly review recent applications of computational free energy prediction methods to enable and guide novel peptide drug and biomarker discovery. We close the review with a brief perspective on the future of computational, structure-based protein-peptide binding affinity prediction. © 2012 John Wiley & Sons A/S. Source

Bayden A.S.,Astrazeneca | Bayden A.S.,CMD Bioscience | Moustakas D.T.,Astrazeneca | Moustakas D.T.,Alkermes | And 3 more authors.
Journal of Chemical Information and Modeling

The SZMAP method computes binding free energies and the corresponding thermodynamic components for water molecules in the binding site of a protein structure [ SZMAP, 1.0.0; OpenEye Scientific Software Inc.: Santa Fe, NM, USA, 2011 ]. In this work, the ability of SZMAP to predict water structure and thermodynamic stability is examined for the X-ray crystal structures of a series of protein-ligand complexes. SZMAP results correlate with higher-level replica exchange thermodynamic integration double decoupling calculations of the absolute free energy of bound waters in the test set complexes. In addition, SZMAP calculations show good agreement with experimental data in terms of water conservation (across multiple crystal structures) and B-factors over a subset of the test set. In particular, the SZMAP neutral entropy difference term calculated at crystallographic water positions within each of the complex structures correlates well with whether that crystallographic water is conserved or displaceable. Furthermore, the calculated entropy of the water probe relative to the continuum shows a significant degree of correlation with the B-factors associated with the oxygen atoms of the water molecules. Taken together, these results indicate that SZMAP is capable of quantitatively predicting water positions and their energetics and is potentially a useful tool for determining which waters to attempt to displace, maintain, or build in through water-mediated interactions when evolving a lead series during a drug discovery program. (Figure Presented). © 2015 American Chemical Society. Source

Diller D.J.,Snowdon Inc. | Diller D.J.,CMD Bioscience | Connell N.D.,Rutgers University | Welsh W.J.,Rutgers University
Journal of Computer-Aided Molecular Design

This report introduces a new ligand-based virtual screening tool called Avalanche that incorporates both shape- and feature-based comparison with three-dimensional (3D) alignment between the query molecule and test compounds residing in a chemical database. Avalanche proceeds in two steps. The first step is an extremely rapid shape/feature based comparison which is used to narrow the focus from potentially millions or billions of candidate molecules and conformations to a more manageable number that are then passed to the second step. The second step is a detailed yet still rapid 3D alignment of the remaining candidate conformations to the query conformation. Using the 3D alignment, these remaining candidate conformations are scored, re-ranked and presented to the user as the top hits for further visualization and evaluation. To provide further insight into the method, the results from two prospective virtual screens are presented which show the ability of Avalanche to identify hits from chemical databases that would likely be missed by common substructure-based or fingerprint-based search methods. The Avalanche method is extended to enable patent landscaping, i.e., structural refinements to improve the patentability of hits for deployment in drug discovery campaigns. © 2015 Springer International Publishing Switzerland. Source

CMD Bioscience | Entity website

2015, CMDBioscience, Inc.5 Science Park, New Haven, CT 06511 All Rights Reserved ...

CMD Bioscience | Entity website

2015, CMDBioscience, Inc.5 Science Park, New Haven, CT 06511 All Rights Reserved ...

Discover hidden collaborations