Homology Modeling, Docking Studies and Molecular Dynamic Simulations Using Graphical Processing Unit Architecture to Probe the Type‐11 Phosphodiesterase Catalytic Site: A Computational Approach for the Rational Design of Selective Inhibitors

Abstract

Phosphodiesterase 11 (PDE11) is the latest isoform of the PDEs family to be identified, acting on both cyclic adenosine monophosphate and cyclic guanosine monophosphate. The initial reports of PDE11 found evidence for PDE11 expression in skeletal muscle, prostate, testis, and salivary glands; however, the tissue distribution of PDE11 still remains a topic of active study and some controversy. Given the sequence similarity between PDE11 and PDE5, several PDE5 inhibitors have been shown to cross-react with PDE11. Accordingly, many non-selective inhibitors, such as IBMX, zaprinast, sildenafil, and dipyridamole, have been documented to inhibit PDE11. Only recently, a series of dihydrothieno[3,2-d]pyrimidin-4(3H)-one derivatives proved to be selective toward the PDE11 isoform. In the absence of experimental data about PDE11 X-ray structures, we found interesting to gain a better understanding of the enzyme-inhibitor interactions using in silico simulations. In this work, we describe a computational approach based on homology modeling, docking, and molecular dynamics simulation to derive a predictive 3D model of PDE11. Using a Graphical Processing Unit architecture, it is possible to perform long simulations, find stable interactions involved in the complex, and finally to suggest guideline for the identification and synthesis of potent and selective inhibitors.

New insights into the structure of the trace amine‐associated receptor 2: Homology modelling studies exploring the binding mode of 3‐iodothyronamine

“…The quality of the models was evaluated following a computational procedure we previously described around concerning other GPCR models …”

Further Insights in the Binding Mode of Selective Inhibitors to Human PDE4D Enzyme Combining Docking and Molecular Dynamics

“…The simulations were performed at neutral pH, with histidines 164 and 200 protonated at δ position to coordinate the Zn 2+ ion. The water molecule between the two ions was treated as hydroxide ion as suggested by studies of Li et al., and by MD simulations studies on PDE11 performed by some of us . Since HIS 160, close to the hydroxide ion, can readily capture a proton, it was protonated at both δ and ϵ positions.…”

Design, Synthesis, and Evaluation of Thyronamine Analogues as Novel Potent Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists

“…This computational option is very useful when one wishes to build a homology model in the presence of a ligand docked into the primary template and has been widely and fruitfully used by us to build GPCR as well as various enzyme models. 33,34 More specifically, in this work, the GPCR 3D structure was generated using 3PDS β 2 -adrenoreceptor as template, following the procedure we previously applied for the development of the human TAAR1 model 33 Similarly, the mTAAR1 model was built and refined in the presence of T1AM properly placed into the 3PDS β 2 -adrenoreceptor binding site by docking procedures. In this way, we can safely assume that we were able to build a much better mTAAR1 binding site for the in silico analysis of the new derivatives than using standard homology modeling protocols.…”