Free Energy-Based Methods
to Understand Drug Resistance
Mutations
Elvis A. F. Martis and Evans C. Coutinho
Abstract In this chapter, we present an overview of various computational
methods, particularly, those that are used to compute the free energy of binding to
understand target site mutations that will enable us to foresee mutations that could
significantly affect drug binding. We begin by looking at the driving forces that lead
to drug resistance and throw some light on the various mechanisms by which drugs
can be rendered ineffective. Next, we studied molecular dynamic simulations and its
use to understand the thermodynamics of protein–ligand interactions. Building on
these fundamentals, we discuss various methods that are available to compute the
free energy binding, their mathematical formulations, the practical aspects of each
these methods and finally their use in understanding drug resistance.
Keywords Molecular dynamics Á Drug resistance Á MM-PB(GB)-SA
Free energy perturbation Á Linear interaction energy Á Computational mutational
scanning Á Thermodynamic integration
1 Drug Resistance Problem
Every organism attempts to survive in hostile conditions by making minor modifications in its life cycle. Though these modifications are observed phenotypically,
genetic reshuffling and alterations are the underlying cause of these changes.
Although we are unable to accurately explain this phenomenon and its initiation, we
have been able to use this observed knowledge and empirically derive explanations
for such modifications. However, it may not always be necessary to know all the
details regarding genetic modifications, so long as we can correctly, at least
empirically, understand such observations, and put it to effective use to predict and
understand the drug resistance problem. Often the enzymes in the biochemical
E. A. F. Martis Á E. C. Coutinho (&)
Molecular Simulations Group, Department of Pharmaceutical Chemistry,
Bombay College of Pharmacy, Kalina, Santacruz [E], Mumbai 400098, India
e-mail: evans.coutinho@bcp.edu.in
© Springer Nature Switzerland AG 2019
C. G. Mohan (ed.), Structural Bioinformatics: Applications in Preclinical Drug
Discovery Process, Challenges and Advances in Computational Chemistry
and Physics 27, https://doi.org/10.1007/978-3-030-05282-9_1
1
to Understand Drug Resistance
Mutations
Elvis A. F. Martis and Evans C. Coutinho
Abstract In this chapter, we present an overview of various computational
methods, particularly, those that are used to compute the free energy of binding to
understand target site mutations that will enable us to foresee mutations that could
significantly affect drug binding. We begin by looking at the driving forces that lead
to drug resistance and throw some light on the various mechanisms by which drugs
can be rendered ineffective. Next, we studied molecular dynamic simulations and its
use to understand the thermodynamics of protein–ligand interactions. Building on
these fundamentals, we discuss various methods that are available to compute the
free energy binding, their mathematical formulations, the practical aspects of each
these methods and finally their use in understanding drug resistance.
Keywords Molecular dynamics Á Drug resistance Á MM-PB(GB)-SA
Free energy perturbation Á Linear interaction energy Á Computational mutational
scanning Á Thermodynamic integration
1 Drug Resistance Problem
Every organism attempts to survive in hostile conditions by making minor modifications in its life cycle. Though these modifications are observed phenotypically,
genetic reshuffling and alterations are the underlying cause of these changes.
Although we are unable to accurately explain this phenomenon and its initiation, we
have been able to use this observed knowledge and empirically derive explanations
for such modifications. However, it may not always be necessary to know all the
details regarding genetic modifications, so long as we can correctly, at least
empirically, understand such observations, and put it to effective use to predict and
understand the drug resistance problem. Often the enzymes in the biochemical
E. A. F. Martis Á E. C. Coutinho (&)
Molecular Simulations Group, Department of Pharmaceutical Chemistry,
Bombay College of Pharmacy, Kalina, Santacruz [E], Mumbai 400098, India
e-mail: evans.coutinho@bcp.edu.in
© Springer Nature Switzerland AG 2019
C. G. Mohan (ed.), Structural Bioinformatics: Applications in Preclinical Drug
Discovery Process, Challenges and Advances in Computational Chemistry
and Physics 27, https://doi.org/10.1007/978-3-030-05282-9_1
1