SPINACH ON THE CEILING: A Theoretical Chemist's Return to Biology

Abstract

I was born in Vienna and came to the United States as a refugee in October 1938. This experience played an important role in my view of the world and my approach to science: It contributed to my realization that it was safe to stop working in fields that I felt I understood and to focus on different areas of research by asking questions that would teach me and others something new. I describe my experiences that led me from chemistry and physics back to my first love, biology, and outline some of the contributions I have made as part of my ongoing learning experience.

The Semiempirical Quantum Mechanical Scoring Function for In Silico Drug Design

“…Thanks to the pioneering work of Martin Karplus, Arieh Warshel, Schneior Lifson and others (reviewed in Ref. [50]), many extensions of MM, includ- CHEMPLUSCHEM MINIREVIEWS www.chempluschem.org ing molecular dynamics (MD), are now routinely used. The idea of MD is to solve Newton's equations of motion to simulate protein fluctuations and movements in time.…”

“…[2] Ligands are often reversible competitive inhibitors of enzymes binding into the proteins' active sites to form a complex. The binding can be experimentally characterised by a dissociation constant (K i ) or IC 50 values. Biochemical enzymological methods or modern biophysical methods, such as isothermal titration calorimetry (ITC) [3] or surface plasmon resonance (SPR), [4] can be used.…”

“…Biochemical enzymological methods or modern biophysical methods, such as isothermal titration calorimetry (ITC) [3] or surface plasmon resonance (SPR), [4] can be used. K i and IC 50 values are related to the change in the Gibbs free energy of binding of the inhibitor to the protein (DG bind ), which can be determined by using computational tools. K i can be directly converted to DG bind using Equation (1):…”

“…The convenient and popular IC 50 values should first be converted to K i . It is possible to use the Cheng and Prusoff equation [Eq.…”

“…In the case of tight-binding inhibitors, however, the enzyme concentration [E] must also be considered. For tight-binding competitive inhibitors, IC 50 can thus be converted to K i by Equation (3): [6] K i ¼ ðIC 50 À½E=2Þ=ð1 þ ½S=K M Þ ð 3Þ…”