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Computational Methods Applied to Rational Drug Design.

ABSTRACT: Due to the synergic relationship between medical chemistry, bioinformatics and molecular simulation, the development of new accurate computational tools for small molecules drug design has been rising over the last years. The main result is the increased number of publications where computational techniques such as molecular docking, de novo design as well as virtual screening have been used to estimate the binding mode, site and energy of novel small molecules. In this work I review some tools, which enable the study of biological systems at the atomistic level, providing relevant information and thereby, enhancing the process of rational drug design.

SUBMITTER: Ramirez D

PROVIDER: S-EPMC5039900 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Computational Methods Applied to Rational Drug Design.

Ramírez David D

The open medicinal chemistry journal 20160426

Due to the synergic relationship between medical chemistry, bioinformatics and molecular simulation, the development of new accurate computational tools for small molecules drug design has been rising over the last years. The main result is the increased number of publications where computational techniques such as molecular docking, <i>de novo</i> design as well as virtual screening have been used to estimate the binding mode, site and energy of novel small molecules. In this work I review some ...[more]

PMID: 27708723

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Project description:SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, -8.7 kcal/mol), PLpro (binding energy, -7.9 kcal/mol), and Nucleocapsid (binding energy, -7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, -24.42 kcal/mol and MMPBSA, -10.80 kcal/mol), PLpro (MMGBSA, -48.69 kcal/mol and MMPBSA, -38.17 kcal/mol) and Nucleocapsid (MMGBSA, -30.05 kcal/mol and MMPBSA, -25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, -22.44 kcal/mol), PLpro (mean, -25.46 kcal/mol), and Nucleocapsid (mean, -23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.

Project description:Although the inhibitors of singly mutated epidermal growth factor receptor (EGFR) kinase are effective for the treatment of non-small cell lung cancer (NSCLC), their clinical efficacy has been limited due to the emergence of various double and triple EGFR mutants with drug resistance. It has thus become urgent to identify potent and selective inhibitors of triple mutant EGFRs resistant to first-, second-, and third-generation EGFR inhibitors. Herein, we report the discovery of potent and highly selective inhibitors of EGFR exon 19 p.E746_A750del/EGFR exon 20 p.T790M/EGFR exon 20 p.C797S (d746-750/T790M/C797S) mutant, which were derived via two-track virtual screening and de novo design. This two-track approach was performed so as to maximize and minimize the inhibitory activity against the triple mutant and the wild type, respectively. Extensive chemical modifications of the initial hit compounds led to the identification of several low-nanomolar inhibitors of the d746-750/T790M/C797S mutant. Among them, two compounds exhibited more than 104-fold selectivity in the inhibition of EGFRd746-750/T790M/C797S over the wild type. The formations of a hydrogen bond with the mutated residue Ser797 and the van der Waals contact with the mutated residue Met790 were found to be a common feature in the interactions between EGFRd746-750/T790M/C797S and the fourth-generation inhibitors. Such an exceptionally high selectivity could also be attributed to the formation of the hydrophobic contact with a Gly loop residue or the hydrogen bond with Asp855 in the activation loop. The discovery of the potent and selective EGFRd746-750/T790M/C797S inhibitors were actually made possible by virtue of the modified protein-ligand binding free energy function involving a new hydration free energy term with enhanced accuracy. The fourth-generation EGFR inhibitors found in this work are anticipated to serve as a new starting point for the discovery of anti-NSCLC medicines to overcome the problematic drug resistance.

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Computational Methods Applied to Rational Drug Design.

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Computational Methods Applied to Rational Drug Design.

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