Experimental Free Ligand Conformations: A Missing Link in Structure-Based Drug Discovery

Abstract

In our experience, it is critical that free ligand conformational information is available to chemists within a timeframe consistent with 'design, make, test, analyze' cycle times of typical drug discovery projects "

Identification of 13 Guanidinobenzoyl- or Aminidinobenzoyl-Containing Drugs to Potentially Inhibit TMPRSS2 for COVID-19 Treatment

“…Compared with Camostat and Nafamostat, Gabexate, which contains an arginine-like side-chain, showed only a weak inhibitory potency [9,11]. Considering that a drug's rigidity is crucial for high-affinity binding due to its low conformational entropy effect [33][34][35], we preferentially considered drugs with guanidinobenzoyl or aminidinobenzoyl rather than an arginineor lysine-like side-chain group; the former two groups have far fewer degrees of freedom and are, hence, more rigid. We searched DrugBank for FDA-approved or investigational drugs that contain guanidinobenzoyl or guanidinobenzoyl and obtained a small library of 13 drugs (Figure 3).…”

Nuclear magnetic resonance free ligand conformations and atomic resolution dynamics

“…Comparisons between experimental and computed NMR parameter values (shifts, NOEs, J couplings) can identify relative populations of conformers, such as a singular, highly populated conformation, with well-defined internuclear distances and torsion angles or an averaged solution structure, composed of multiple conformations, each at a low molar fraction of the total, resulting from low barriers to rotation around bonds. NMR analysis of molecular flexibility in solution (NAM-FIS; Cicero et al, 1995) takes the approach of systematically varying percent contributions from sets of conformers generated in-silico, together with the corresponding calcu-lated NMR parameter values, compared against the experimental data. The sum of square differences determines the goodness-of-fit between experimental and calculated values to select a best-fit population-weighted model.…”

“…The sum of square differences determines the goodness-of-fit between experimental and calculated values to select a best-fit population-weighted model. The fundamental concept of filtering theoretical conformations through experimental data to derive the best fit has become well established over the decades, together with variations in details of implementation, to determine the conformational preference(s) of a small molecule in solution (Cicero et al, 1995;Nevins et al, 1999;Slabber et al, 2016;Wu et al, 2017;Balazs et al, 2019;Farès et al, 2019;Atilaw et al, 2021).…”

Comment on mr-2021-27

“…Determining the conformational profile of a free ligand in solution enhances early drug discovery programs (LaPlante et al, 2014;Blundell et al, 2016;Foloppe and Chen, 2016;Chiarparin et al, 2019). A general overview of how NMR fits into Medicinal Chemistry design cycles is illustrated in Fig.…”

“…Molecular rigidification strategies (Fang et al, 2014;de Sena M Pinheiro et al, 2019) increase pre-organization and NMR conformational analysis can deconvolute and report on the molar fraction adopting the bioactive conformation. Structure based drug design (SBDD) can be enhanced by ready access to 3D free ligand average solution conformations to complement X-ray crystallographic models of the bound ligand and proteinligand interactions (Blundell et al, 2013;Chiarparin et al, 2019;Balazs et al, 2019). Faster design cycles require quick turnover times in analyzing solution conformations of synthesized compounds.…”