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Strategies for lead discovery: application of footprint similarity targeting HIVgp41.

ABSTRACT: A highly-conserved binding pocket on HIVgp41 is an important target for development of anti-viral inhibitors. Holden et al. (Bioorg. Med. Chem. Lett.2012, 22, 3011) recently reported 7 experimentally-verified leads identified through a computational screen to the gp41 pocket in conjunction with a new DOCK scoring method (termed FPS scoring) developed in our laboratory. The method employs molecular footprints based on per-residue van der Waals interactions, electrostatic interactions, or the sum. In this work, we critically examine the gp41 screening results, prioritized using different scoring methods, in terms of two main criteria: (1) ligand pose properties which include footprint and energy score decompositions, MW, number of rotatable bonds, ligand efficiency, formal charge, and volume overlap, and (2) ligand pose stability which includes footprint stability (changes in footprint overlap) and rmsd stability (changes in geometry). Relative to standard DOCK scoring, pose property analyses demonstrate how FPS scoring can be used to identify ligands that mimic a known reference (derived here from the native gp41 substrate), while pose stability analyses demonstrate how FPS scoring can be used to enrich for compounds with greater overall stability during molecular dynamics (MD) simulations. Compellingly, of the 115 compounds tested experimentally, the 7 active compounds, as a group, more closely mimic the footprints made by the reference and show greater MD stability compared to the inactive group. Extensive studies using 116 protein-ligand complexes as controls reveal that ligands in their crystallographic binding pose also maintain higher FPS scores and smaller rmsds than do accompanying decoys, confirming that native poses are indeed 'stable' under the same conditions and that monitoring FPS variability during compound prioritization is likely to be beneficial. Overall, the results suggest the new scoring method will complement current virtual screening approaches for both the identification (FPS-ranking) and prioritization (FPS-stability) of target-compatible molecules in a quantitative and logical way.

SUBMITTER: Holden PM

PROVIDER: S-EPMC3913180 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Strategies for lead discovery: application of footprint similarity targeting HIVgp41.

Holden Patrick M PM Allen William J WJ Gochin Miriam M Rizzo Robert C RC

Bioorganic & medicinal chemistry 20131026 1

A highly-conserved binding pocket on HIVgp41 is an important target for development of anti-viral inhibitors. Holden et al. (Bioorg. Med. Chem. Lett.2012, 22, 3011) recently reported 7 experimentally-verified leads identified through a computational screen to the gp41 pocket in conjunction with a new DOCK scoring method (termed FPS scoring) developed in our laboratory. The method employs molecular footprints based on per-residue van der Waals interactions, electrostatic interactions, or the sum. ...[more]

PMID: 24315195

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Project description:Fragment-based drug (or lead) discovery (FBDD or FBLD) has developed in the last two decades to become a successful key technology in the pharmaceutical industry for early stage drug discovery and development. The FBDD strategy consists of screening low molecular weight compounds against macromolecular targets (usually proteins) of clinical relevance. These small molecular fragments can bind at one or more sites on the target and act as starting points for the development of lead compounds. In developing the fragments attractive features that can translate into compounds with favorable physical, pharmacokinetics and toxicity (ADMET-absorption, distribution, metabolism, excretion, and toxicity) properties can be integrated. Structure-enabled fragment screening campaigns use a combination of screening by a range of biophysical techniques, such as differential scanning fluorimetry, surface plasmon resonance, and thermophoresis, followed by structural characterization of fragment binding using NMR or X-ray crystallography. Structural characterization is also used in subsequent analysis for growing fragments of selected screening hits. The latest iteration of the FBDD workflow employs a high-throughput methodology of massively parallel screening by X-ray crystallography of individually soaked fragments. In this review we will outline the FBDD strategies and explore a variety of in silico approaches to support the follow-up fragment-to-lead optimization of either: growing, linking, and merging. These fragment expansion strategies include hot spot analysis, druggability prediction, SAR (structure-activity relationships) by catalog methods, application of machine learning/deep learning models for virtual screening and several de novo design methods for proposing synthesizable new compounds. Finally, we will highlight recent case studies in fragment-based drug discovery where in silico methods have successfully contributed to the development of lead compounds.

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Strategies for lead discovery: application of footprint similarity targeting HIVgp41.

Publications

Strategies for lead discovery: application of footprint similarity targeting HIVgp41.

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