From chemistry-request {*at*} ccl.net Thu Dec 12 15:32:48 1991 Date: Thu, 12 Dec 91 15:07:54 EST From: balbes -x- at -x- osiris.rti.org (Lisa Balbes) To: chemistry[ AT ]ccl.net, sybyl[ AT ]quant.chem.rpi.edu Subject: Rational Drug Design (better late than never) Status: R As promised, I have compiled a summary of references and information I gathered in reading all the responses to my (much) earlier request. All typos and mistakes are mine. A brief index/outline follows - for the entire 282 line file, email me at balbes.,at,.osiris.rti.org ____________________________ Introduction: Steps in rational drug design - 1. Determine receptor site of interest. 2. Build model of active site (receptor). a. Model entire protein - from xray of protein, homology modeling or b. build pharmacophore (geometric description of the minimal requirements of shape and charge complimentarity) 3. Develop inhibitor structures that fit active site model and dock. 4. Quantitate interaction, to predict activity of new compounds. 5. Synthesize compounds; evaluate their activity in the system of interest. 6. Refine (2), repeat (3) - (5). 7. Find effective, safe, synthesizable compound. Patent. Sell. $$$$$$$. Either a) start again at (1) or b) retire to Hawaii. ********** step 2 ******************************* GRID method of Peter J. Goodford ********** step 3 ******************************* Distance Geometry Devloped by Crippen and co-workers ********** step 3 (docking) ********************** DOCK Irwin D. Kuntz, Jr. ********** steps 3, 4 ****************************** GROW method of Moon and Howe (proprietary program, but methods useful). ************* step 4 ************************* Free Energy Perturbation ************* step 4 ************************* Min/MD cycling GENERAL APPROACHES ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Quantitative Structure Activity Relationship (QSAR) Active Analog Approach Simulated Annealing Molecular Dynamics (MD) ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ General Reviews %%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%% standard disclaimer %%%% Lisa M. Balbes, Ph.D. phone: 919-541-6563 Research Triangle Institute, PO Box 12194 vmail: 919-541-6767, xt 6563 Research Triangle Park, NC 27709-2194 email: balbes- at -osiris.rti.org - This came directly from a computer and should not be doubted or disbelieved.-