Computational Studies for Structure-Based Drug Designing Against Transmembrane Receptors: pLGICs and Class A GPCRs

Abstract

Biological cell is the fundamental building block of every living system. The plasma membrane, a phospholipid bilayer consisting of two asymmetric leaflets, defines its existence by separating the interior from the exterior. This low dielectric barrier selectively prevents the passage of hydrophilic and charged compounds including small ions. Integral transmembrane proteins span the entire bilayer and take part in small-molecule transport and complex signaling pathways while functioning as receptors and/or ion channels. These proteins carry important biological functions and hence are attractive drug targets. Present review considers the members of two important protein superfamilies that provided the major pharmaceutical drug-targets, viz., Cys-loop pentameric ligand gated ion channels (pLGICs) and class A G-protein-coupled receptors (GPCRs). The crystal structures of integral membrane proteins (IMPs) are difficult to obtain. Their unavailability has limited the structural investigation and associated structure-based drug designing (SBDD). However, recent advancement in crystallographic techniques yielded some important crystal structures. The advancement of computational science guided IMPs study even in the absence of crystal structures through the homology/comparative modeling approaches. These proteins possess multiple ligand binding sites including both orthosteric and allosteric sites. Addressing the multidimensional problem of understanding the structure and dynamics of such big proteins, multisite-protein-ligand complexes is now possible with molecular dynamics simulation approach, enabled with highly enhanced computational power. Overall the discussion highlights the understanding of structure-function relationship that guides SBDD of these interesting and important transmembrane proteins.

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

“…Interestingly, class A GPCRs contain a 'placeholder' formed by the N-terminus and the extracellular loop 2 (ECL2) [335][336][337]. While adopting an open conformation in the absence of the ligand, the extracellular loop plays a critical role in lipophilic ligand recognition, access, and selectivity for the orthosteric site [338,339]. In the same class, a consensus amino acid network was described through a comprehensive analysis of X-ray structures by Venkatakrishnan et al [340].…”

Insect RDL Receptor Models for Virtual Screening: Impact of the Template Conformational State in Pentameric Ligand-Gated Ion Channels

“…■ DISCUSSION AND CONCLUSIONS Homology modeling approaches have been intensively used for gaining knowledge about the pLGIC structures, in order to elucidate physiologically relevant aspects, such as their gating mechanism 52 and their interactions with ligands. 53 Particularly, in the case of GABA A receptors, efforts have been made to obtain good-quality homology models, 14 both for vertebrate subunits and for the insect RDL homopentamer. The most common assumption in homology modeling is that the template with the highest Seq Id to the target should be selected because it would result in the best obtainable model.…”

“…Homology modeling approaches have been intensively used for gaining knowledge about the pLGIC structures, in order to elucidate physiologically relevant aspects, such as their gating mechanism and their interactions with ligands . Particularly, in the case of GABA A receptors, efforts have been made to obtain good-quality homology models, both for vertebrate subunits and for the insect RDL homopentamer.…”