Accommodating protein flexibility for structure based drug design

Posted by / 12-Aug-2018 11:50

Accommodating protein flexibility for structure based drug design

Ren Wei structure-based drug design structure- 17 Drug Design Methods: molecules to be modified…

Successes and Failures in Structure-Based Drug Design by Ren Wei Ren Wei structure-based drug design structure- 1 overview • Choice of drug target • Determination of the accurate structural information • Identification of the Target Site • Drug Design Methods • Protein and Ligand Flexibility • Some successful examples • Reference Ren Wei structure-based drug design structure- 2 Structure-Based Drug Design: The first success • The first success: peptide-based HIV protease inhibitor; (Roberts, N., 1990) Ren Wei structure-based drug design structure- 3 The process of structure-based drug design: an overview • The Iterative Process of Structure-Based Drug Design Ren Wei structure-based drug design structure- 4 Choice of drug target: modulate function of human protein • closely linked to human disease and binds a small molecule in order to carry out a function; • usually has a well-defined binding pocket; • other designed small molecules can compete, at a required level of potency, with the natural small molecule in order to modulate the function of the target; Ren Wei structure-based drug design structure5 Choice of drug target: modulate function of human protein • Drug target are usually Protein; • Drug design against RNA targets with well-defined secondary structure, like the bacterial ribosome and portions of the HIV genome, has also been effective; Ren Wei structure-based drug design structure- 6 Choice of drug target: modulate function of human protein Main drug products of the current market small molecule drugs against G protein coupled receptors (GPCRs) Small molecules that modulate the function of ion channels, proteases, kinases, and nuclear hormone receptors 22% at least 25% Ren Wei structure-based drug design structure- 7 Choice of drug target: total inhibition against pathogenic organisms Criteria: • Antimicrobial drug targets should be essential, have a unique function in the pathogen, be present only in the pathogen, and be able to be inhibited by a small molecule.• Flexibility programming: Incorporation of multiple protein structure.Ren Wei structure-based drug design structure22 Protein and Ligand Flexibility: Determine ensembles of multiple protein structure • NMR ensembles (s.• In a third capacity, the effect of the solvent can be incorporated into the scoring scheme for the target:ligand interaction.Ren Wei structure-based drug design structure24 Solvent Effects: incorporated to the designed Ligand • Nonpeptide HIV Protease Inhibitors Based on Cyclic Urea Compounds Incorporate an Oxygen Atom Where a Bound Water Molecule Was Visualized in X-Ray Structures; Ren Wei structure-based drug design structure25 Solvent Effects • The steps of increased accuracy in modeling the solvent effect during scoring are as follows: (1) making the assumption that the molecules are in a vacuum, i.e., no solvent modeling; (2) using a fixed dielectric constant in estimating electrostatic contributions; (3) explicit solvation models; (4) modeling the Born equation.

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Additionally, RNA secondary structural can provide excellent target sites since they are species specific, bind ligands, and can be specific for a disease state.

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