Integrating Virtual Screening and Combinatorial Chemistry for Accelerated Drug Discovery

Abstract

Virtual screening is increasingly being used in drug discovery programs with a growing number of successful applications. Experimental methodologies developed to speed up the drug discovery processes include high-throughput screening and combinatorial chemistry. The complementarities between computational and experimental screenings have been recognized and reviewed in the literature. Computational methods have also been used in the combinatorial chemistry field, in particular in library design. However, the integration of computational and combinatorial chemistry screenings has been attempted only recently. Combinatorial libraries (experimental or virtual) represent a notable source of chemically related compounds. Advances in combinatorial chemistry and deconvolution strategies, have enabled the rapid exploration of novel and dense regions in the chemical space. The present review is focused on the integration of virtual and experimental screening of combinatorial libraries. Applications of virtual screening to discover novel anticancer agents and our ongoing efforts towards the integration of virtual screening and combinatorial chemistry are also discussed.

Inhibitors of DNA Methyltransferases: Insights from Computational Studies

“…A number of these amino acid residues are involved in the mechanism of methylation. Based on distance measurements, binding poses, and docking-based energy scanning of different poses of the trajectory, the results support the previous hypothesis that the catalytic cysteine performs a nucleophilic Michael type 1,4 addition to the , -unsaturated carbonyl system of nanaomycin A [76].…”

Molecular Docking and Structure-Based Drug Design Strategies

“…Following the development of the first algorithms in the 1980s, molecular docking became an essential tool in drug discovery [22]. For example, investigations involving crucial molecular events, including ligand binding modes and the corresponding intermolecular interactions that stabilize the ligand-receptor complex, can be conveniently performed [23].…”

“…For example, investigations involving crucial molecular events, including ligand binding modes and the corresponding intermolecular interactions that stabilize the ligand-receptor complex, can be conveniently performed [23]. Furthermore, molecular docking algorithms execute quantitative predictions of binding energetics, providing rankings of docked compounds based on the binding affinity of ligand-receptor complexes [22,23]. The identification of the most likely binding conformations requires two steps: (i) exploration of a large conformational space representing various potential binding modes; (ii) accurate prediction of the interaction energy associated with each of the predicted binding conformations [24].…”

Molecular Aspects of Opioid Receptors and Opioid Receptor Painkillers

“…(Brooijmans and Kuntz 2003) Computational methods are largely applied to corporate chemical collections (Bajorath 2002) as well as combinatorial chemical libraries. (Houghten, Pinilla et al 2008) However, limited efforts have been reported so far to explicitly integrate information from mixture-based combinatorial libraries and computational techniques (López-Vallejo, Caulfield et al 2011;Yongye, Pinilla et al 2011). The structural analogy contained in combinatorial libraries in general and in mixture-based libraries in particular deserves particular considerations.…”