Baltimore, MD, 15 November 2016 – Version 2.0.0 is the second release of CGenFF program, extending support to a larger variety of drug-like molecules to be used routinely in Computer-Aided Drug Design projects. Specifically, it improves treatment of halogen bonds, by introducing lone-pairs onto the halogen atoms of aromatic systems. Additionally, support is now extended to four-membered oxetane and glycoluril moieties. This is driven largely by improvements in the newly released version 4.0 of CGenFF force field. The following is the detailed list of changes:
Introduction of lone pairs on halogen atoms
Halogen atoms are often used in drug-design campaigns for their capability to improve oral absorption, while simultaneously retaining/improving potency. Due to the atom-centered point charge approach, previous empirical force fields have inadequately characterized the sigma-hole driven halogen-bond interactions. To overcome this, a positively charged virtual particle is now attached to the halogens that decorate aromatic systems. This lone-pair treatment was developed based on phenyl-X analogs, with X being Cl, Br or I including di- and tri-halogenated species. Inclusion of positive virtual sites on halogens was shown to lead to better agreement with quantum mechanical data as well as across experimental observables, including preservation of ligand binding poses as a direct result of the improved representation of halogen bonding. For details about the parameterization of the virtual particle on halogen, please refer to: Gutiérrez, IS, et al., Bioorg. Med. Chem. 24.20 (2016): 4812-4825. DOI: 10.1016/j.bmc.2016.06.034.
Support of four-membered oxetane rings
Oxetane moiety has been found to significantly enrich the medicinal chemistry toolbox due to its capability of exerting potentially far-reaching property-modulating effects. Oxetane ring has been explicitly parameterized in the 4.0 version of the CGenFF force-field. OG3C51 atom-type from the five-membered furanose was used to delineate oxygen in the ring, after explicit fitting of partial atomic charges and ring-dihedrals.
Support of glycoluril
Glycoluril is an important part of several host-guest molecular clips and drug-delivery vehicles. Partial atomic charges and dihedral parameters of the glycoluril ring has been explicitly parameterized in the 4.0 version of the CGenFF force field. Absolute binding free energy calculations of CBClip host-guest systems have been found to improve with the application of these new parameters. For details about the parameterization of glycolruil, please refer to: Lee, J, et al., J Comput Aided Mol Des (2016): 1-15. DOI: 10.1007/s10822-016-9968-2.
About SilcsBio, LLC: SilcsBio started operations in April 2013 based on licensed intellectual property developed by Dr. Alexander D. MacKerell, Jr at the University of Maryland, Baltimore where he is the Grollman-Glick Professor of Pharmaceutical Sciences and Director of the Computer-Aided Drug Design Center. The company is headquartered at Spark-Baltimore located at 8 Market Place, Suite 300, Baltimore, MD 21202.
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