ABSTRACT
The understanding of binding interactions between any protein and a small molecule plays a key role in the rationalization of affinity and selectivity. It is essential for an efficient structure-based drug design (SBDD) process. FMO enables ab initio approaches to be applied to systems that conventional quantum-mechanical (QM) methods would find challenging. The key advantage of the Fragment Molecular Orbital Method (FMO) is that it can reveal atomistic details about the individual contributions and chemical nature of each residue and water molecule toward ligand binding which would otherwise be difficult to detect without using QM methods. In this chapter, we demonstrate the typical use of FMO to analyze 19 crystal structures of ß1 and ß2 adrenergic receptors with their corresponding agonists and antagonists.
Subject(s)
Drug Design , Drug Discovery , Ligands , Algorithms , Drug Discovery/methods , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , Quantitative Structure-Activity Relationship , Receptors, G-Protein-Coupled/metabolismABSTRACT
The reliable and precise evaluation of receptor-ligand interactions and pair-interaction energy is an essential element of rational drug design. While quantum mechanical (QM) methods have been a promising means by which to achieve this, traditional QM is not applicable for large biological systems due to its high computational cost. Here, the fragment molecular orbital (FMO) method has been used to accelerate QM calculations, and by combining FMO with the density-functional tight-binding (DFTB) method we are able to decrease computational cost 1000 times, achieving results in seconds, instead of hours. We have applied FMO-DFTB to three different GPCR-ligand systems. Our results correlate well with site directed mutagenesis data and findings presented in the published literature, demonstrating that FMO-DFTB is a rapid and accurate means of GPCR-ligand interactions. © 2017 Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.
ABSTRACT
Although unusual somatic preoccupations can be seen in somatoform disorders and obsessive-compulsive disorder (OCD), unwanted penile erections have been described only in two cases of OCD, both adults. In the present case an 8-year-old boy developed unwanted erections, other obsessive-compulsive symptoms, as well as symptoms of posttraumatic stress disorder, such that he met criteria for both disorders. Treatment consisted of sertraline combined with individual play therapy and family therapy, following which the patient reported modest improvement in symptoms of both disorders.
