Rule of 5 review电子版.pdf

insight review articles Navigating chemical space for biology and medicine Christopher Lipinski1 Andrew Hopkins2 1Pfizer Global RD, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA (e-mail: christopher_a_lipinski@) 2Pfizer Global RD, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK (e-mail: andrew.hopkins@) Despite over a century of applying organic synthesis to the search for drugs, we are still far from even a cursory examination of the vast number of possible small molecules that could be created. Indeed, a thorough examination of all ‘chemical space’ is practically impossible. Given this, what are the best strategies for identifying small molecules that modulate biological targets? And how might such strategies differ, depending on whether the primary goal is to understand biological systems or to develop potential drugs? he relationship between chemistry, biology and examination of all the possible organic compounds that medicine has been remarkably productive over comprise ‘chemical space’ (Box 1). Chemical space is for all the past century, since Paul Ehrlich pioneered the practical purposes infinite and limited only by the chemist’s idea of systematically searching for drugs. By imagination. Tscreening just over 600 synthetic compounds, Not all biologically active compounds have the desired Ehrlich discovered arsphenamine (Salvarsan)1, which physicochemical properties to be a drug. A biologically active greatly improved the treatment of syphilis. Researchers now compound may be too lipophilic (greasy) to be orally routinely screen millions of compounds in the search for