Title:First-Principles Modeling of Biological Systems and Structure-Based Drug-Design
VOLUME: 9 ISSUE: 1
Author(s):Jacopo Sgrignani and Alessandra Magistrato
Affiliation:CNR-IOM-Democritos National Simulation Center c/o International School for Advanced Studies (SISSA/ISAS), Trieste, Italy.
Keywords:Anticancer drugs, metallo-β-lactamases, metal-based drug, metallo-enzymes, neurodegenerative diseases, QM/MM
methods, structure-based drug design, α4β2 nicotinic receptor, biological system, drug targeting
Abstract:Molecular modeling techniques play a relevant role in drug design providing detailed information at atomistic
level on the structural, dynamical, mechanistic and electronic properties of biological systems involved in diseases’ onset,
integrating and supporting commonly used experimental approaches. These information are often not accessible to the
experimental techniques taken singularly, but are of crucial importance for drug design. Due to the enormous increase of
the computer power in the last decades, quantum mechanical (QM) or first-principles-based methods have become often
used to address biological issues of pharmaceutical relevance, providing relevant information for drug design. Due to their
complexity and their size, biological systems are often investigated by means of a mixed quantum-classical (QM/MM)
approach, which treats at an accurate QM level a limited chemically relevant portion of the system and at the molecular
mechanics (MM) level the remaining of the biomolecule and its environment. This method provides a good compromise
between computational cost and accuracy, allowing to characterize the properties of the biological system and the (free)
energy landscape of the process in study with the accuracy of a QM description. In this review, after a brief introduction
of QM and QM/MM methods, we will discuss few representative examples, taken from our work, of the application of
these methods in the study of metallo-enzymes of pharmaceutical interest, of metal-containing anticancer drugs targeting
the DNA as well as of neurodegenerative diseases. The information obtained from these studies may provide the basis for
a rationale structure-based drug design of new and more efficient inhibitors or drugs.
