Free-energy calculations in structure-based drug design

doi:10.1017/CBO9780511730412.007

5 - Free-energy calculations in structure-based drug design

from PART II - COMPUTATIONAL CHEMISTRY METHODOLOGY

Published online by Cambridge University Press: 06 July 2010

Michael R. Shirts ,

David L. Mobley and

Scott P. Brown

Edited by

Kenneth M. Merz, Jr ,

Dagmar Ringe and

Charles H. Reynolds

Show author details

Kenneth M. Merz, Jr: Affiliation:
University of Florida
Dagmar Ringe: Affiliation:
Brandeis University, Massachusetts
Charles H. Reynolds: Affiliation:
Johnson & Johnson Pharmaceutical Research & Development

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Summary

INTRODUCTION

The ultimate goal of structure-based drug design is a simple, robust process that starts with a high-resolution crystal structure of a validated biological macromolecular target and reliably generates an easily synthesized, high-affinity small molecule with desirable pharmacological properties. Although pharmaceutical science has made significant gains in understanding how to generate, test, and validate small molecules for specific biochemical activity, such a complete process does not now exist. In any drug design project, enormous amounts of luck, intuition, and trial and error are still necessary.

For any small molecule to be considered a likely drug candidate, it must satisfy a number of different absorption/distribution/metabolism/excretion (ADME) properties and have a good toxicological profile. However, a small molecule must above all be active, which in most cases means that it must bind tightly and selectively to a specific location in the protein target before any of the other important characteristics are relevant. To design a drug, large regions of chemical space must be explored to find candidate molecules with the desired biological activity. High-throughput experimental screening methods have become the workhorse for finding such hits. However, their results are limited by the quality and diversity of the preexisting chemical libraries, which may contain only molecules representative of a limited portion of the relevant chemical space for a given target. Combinatorial libraries can be produced to supplement these efforts, but their use requires careful design strategies and they are subject to a number of pitfalls.

Type: Chapter
Information: Drug Design
Structure- and Ligand-Based Approaches
, pp. 61 - 86

DOI: https://doi.org/10.1017/CBO9780511730412.007 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2010

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