Computational Drug Structure Activity Relationship (SAR)

  Learning Goal: Through the practice of structure activity relationship (SAR) studies, identify how changing functional groups can impact the molecular properties of a drug and develop a picture of the drug’s binding site. Background: An important step that is often undertaken in the design and development of drugs is a structure activity relationship (SAR) analysis. SAR analysis involves the process of removing, replacing and/or adding functional groups around a drug or pharmacophore and provides information on the structure of the binding site as well as the drug’s pharmacokinetics. Molinspiration (https://www.molinspiration.com/cgi-bin/properties) is a free on-line tool for calculation of important molecular properties (logP, polar surface area (PSA), number of hydrogen bond donors (HBD) and acceptors (HBA) and others), as well as prediction of bioactivity score for the six most important drug targets: GPCR ligands, kinase inhibitors, ion channel modulators, nuclear receptors, protease inhibitors, and enzyme inhibitors. LogP is a measure of a substance’s hydrophobicity/hydrophilicity. LogP is obtained from taking the Log10 of the ratio of solubility of substance in a mixture of non-polar (octanol) and polar (water) solvents as per the following equation: LogP=Log_10 (([solute]_octanol)/([solute]_water )) The equation indicates the greater the LogP of a substance, the more hydrophobic. LogP is a useful measure in medicinal chemistry as it provides a guide to bioavailability and distribution of a drug. Most drugs have a LogP value in the range of 0 and 5. A GPCR ligand binds to G-protein-coupled receptors (GPCR) and interfering with the cell signalling process. An ion channel modulator binds to ion channel receptors that allow ions to cross a cell membrane. Ion channel modulators cause ion channels to close or open. Kinase inhibitors modulate activity of kinase-linked receptors, a cell-surface receptor with intracellular domains that are associated with an enzyme. Kinase is a specific type of enzyme normally associated with cell growth and cancer. Kinase inhibitors are designed as anticancer drugs. A nuclear receptor ligand binds to nuclear receptors that are found in the cell nucleus and regulate gene transcription. A protease inhibitor modulates the activity of proteases, enzymes that break down protein chains (i.e. HIV-1 protease). Enzyme inhibitor: Many drugs inhibit enzymes but are not specifically kinase inhibitors (anticancer) or protease inhibitors (anti-HIV). An enzyme inhibitor is a catch-all category for any molecule that likely binds and blocks enzymes. Exercise: The goal of this task is to conduct a small SAR study with respect to known drugs and their activity toward their target site and their physical properties. The information obtained from the SAR study will provide clues to the structure of the target site and how the drug may bind to its target as well an appreciation of how differing functional groups may impact the physical properties of molecule. Method: Select one of the six known drugs listed in the table 1. The drugs’ structure and common target site is provided. Draw the structure of the drug in the Molinspiration app and investigate and report on its calculated properties and predicted bioactivity. Conduct a simple SAR study on your drug of choice by adding, removing, or replacing functional groups on your drug. Provide rationale for the modification you made to the drug. Using the Molinspiration app, inspect any changes to the compound’s properties and predicted bioactivity at its target site. Try to draw chemically stable structures. In general, the non-carbon atoms found in drugs tend to be connected to carbon atoms (not each other). For example, an N-Cl bond would not be found in a drug. Do not submit structures with charged atoms. Compare and comment on the changes to the physical properties and bioactivity observed between the original drug and your new compound and provide some plausible rationale relating the potential activity of the drug.