From Homology Models to a Set of Predictive Binding Pockets–a 5-HT_1A Receptor Case Study

Abstract

Despite its remarkable importance in the arena of drug design, serotonin 1A receptor (5-HT1A) has been elusive to the x-ray crystallography community. This lack of direct structural information not only hampers our knowledge regarding the binding modes of many popular ligands (including endogenous neurotransmitter – serotonin), but also limits the search for more potent compounds. In this paper we shed new light on the 3D pharmacological properties of the 5-HT1A receptor by using a ligand-guided approach (ALiBERO) grounded in the Internal Coordinate Mechanics (ICM) docking platform. Starting from a homology template and set of known actives, the method introduces receptor flexibility via Normal Mode Analysis and Monte Carlo sampling, to generate a subset of pockets that display enriched discrimination of actives from inactives in retrospective docking. Here, we thoroughly investigated the repercussions of using different protein templates and the effect of compound selection on screening performance. Finally, the best resulting protein models were applied prospectively in a large virtual screening campaign, in which two new active compounds were identified that were chemically distinct from those described in the literature.

Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach

“…The orthosteric binding site of serotonin receptors is well known [11,23,[45][46][47][48][49][50][51][52] especially in the context of ligands having basic nitrogen in the structure, e.g., long-chain arylpiperazines [23,45,46,[49][50][51][52]. Among all serotoninergic receptors, the structure of only three has been resolved so far.…”

“…In addition, the FMO methodology allowed complementing or confirming the nature of interactions, postulated so far as crucial for the 5-HT 1A receptor. For example, the interaction with S5.42, which was considered as a polar and core contact [48,56], caused stabilization of the L-R complex. Contact with N7.39, which was often engaged in ligand binding, being either an acceptor of hydrogen bond [22,24] or forming dipoledipole interaction [48], based on the FMO calculations is a highly attractive interaction.…”

“…For example, the interaction with S5.42, which was considered as a polar and core contact [48,56], caused stabilization of the L-R complex. Contact with N7.39, which was often engaged in ligand binding, being either an acceptor of hydrogen bond [22,24] or forming dipoledipole interaction [48], based on the FMO calculations is a highly attractive interaction. Comparison between serotonin receptorsa case study for ligand 1 For ligand 1, the in vitro activities towards the studied receptors are known ( Fig.…”

“…However, the repulsive nature of interaction with tyrosine 7.43 was unexpected. After all, this contact is observed both in 5-HT 1B and 5-HT 2B crystals [53][54][55] and is mentioned in many modeling studies for various serotonin receptors [11,23,[45][46][47][48][49][50][51]. Considering, for example, the 5-HT 1A receptor (Table 3), docking studies indicated a specific π-π or π-CH hydrophobic interaction [48,56], while optimization of the binding site using the ONIOM method even showed the possibility to form hydrogen bonding to the ligand [22].…”

Artificial intelligence and big data facilitated targeted drug discovery

“…Its application is very promising, such as the identification of conserved binding pockets in ricin A chain,23 RASSF2 potential binding pocket prediction24 and so on. There are two ways to find a pocket combination: (1) proteins with known 3D structures can be searched from the PDB database,25 and related information can be downloaded directly from the database; and (2) method of homology modelling, using I-TASSER, SwissModel, ModWeb and other online servers based on homologous modelling to generate protein 3D structure, as well as to predict the ligand-binding pocket, for example, prediction of serotonin 1A receptor binding pocket 26…”