Hagler A.T.,University of Massachusetts Amherst |
Hagler A.T.,Shifa Biomedical Corporation
Journal of Chemical Theory and Computation | Year: 2015
Computer simulations are increasingly prevalent, complementing experimental studies in all fields of biophysics, chemistry, and materials. Their utility, however, is critically dependent on the validity of the underlying force fields employed. In this Perspective we review the ability of quantum mechanics, and in particular analytical ab initio derivatives, to inform on the nature of intra- and intermolecular interactions. The power inherent in the exploitation of forces and second derivatives (Hessians) to derive force fields for a variety of compound types, including inorganic, organic, and biomolecules, is explored. We discuss the use of these quantities along with QM energies and geometries to determine force constants, including nonbond and electrostatic parameters, and to assess the functional form of the energy surface. The latter includes the optimal form of out-of-plane interactions and the necessity for anharmonicity, and terms to account for coupling between internals, to adequately represent the energy of intramolecular deformations. In addition, individual second derivatives of the energy with respect to selected interaction coordinates, such as interatomic distances or individual dihedral angles, have been shown to select out for the corresponding interactions, annihilating other interactions in the potential expression. Exploitation of these quantities allows one to probe the individual interaction and explore phenomena such as, for example, anisotropy of atom-atom nonbonded interactions, charge flux, or the functional form of isolated dihedral angles, e.g., a single dihedral X-C-C-Y about a tetrahedral C-C bond. © 2015 American Chemical Society.
Shifa Biomedical Corporation | Date: 2014-03-11
Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), as well as therapeutic methods for use of such compounds to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia. Examples of compounds include thiadiazole, isoxazole, 1,2,4-triazole, thiazole, indole, pyrazole, and pyrrolinone derivatives.
Shifa Biomedical Corporation | Date: 2014-03-04
Compositions and methods for synthesizing virus-like particles (VLPs) and methods of use thereof are provided.
Shifa Biomedical Corporation | Date: 2014-03-11
Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), and methods of using these modulators to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.34M | Year: 2010
DESCRIPTION (provided by applicant): Heart disease is the leading cause of death for both men and women in the US, accounting for nearly 40% of all annual deaths. A high cholesterol level is well-known risk factors for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, of which statins are the leading drugs, only 38% of patients taking these drugs are achieving the low-density lipoprotein cholesterol goals set by the National Cholesterol Education Program (NCEP). Furthermore, patients with homozygous familial hypercholesterolemia who have markedly elevated cholesterol levels respond poorly to current drug therapy, and are at very high risk of premature cardiovascular disease. These and other patients will dramatically benefit from an aggressive treatment of hypercholesterolemia. The long-term goal of this work is to develop novel drugs for cholesterol lowering. Our therapeutic target is the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 controls the degradation of the LDL receptor (LDLR) in the liver and thereby contributes to cholesterol homeostasis. PCSK9 is synthesized as a precursor protein that undergoes processing between the prodomain and catalytic domain. This processing is required for PCSK9 to be secreted and to undertake its biological activity. Our goal is to identify compounds that prevent the processing of PCSK9, thus prevent its secretion and its ability to participate in the degradation of the LDL receptor. To achieve our Phase I goal, we have integrated virtual (computer) screening methods with cell-based assays and consequently identified five screening hits. As part of this Phase II proposal, we plan to expand and optimize our hits, and confirm the ability of selected compounds to stabilize the LDLR and decrease the LDL-C level using in situ and in vivo studies. PUBLIC HEALTH RELEVANCE: Heart disease is the leading cause of death for both men and women in the US. A high cholesterol level is a well-known risk factor for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, these drugs do not treat a segment of the population with very high cholesterol. Our goal is to develop new cholesterol lowering drugs that have an effect on all individuals with high cholesterol levels, including that segment of the population having very high cholesterol levels.