Data driven polypharmacological drug design for lung cancer: analyses for targeting ALK, MET, and EGFR.

Drug design of protein kinase inhibitors is now greatly enabled by thousands of publicly available X-ray structures, extensive ligand binding data, and optimized scaffolds coming off patent. The extensive data begin to enable design against a spectrum of targets (polypharmacology); however, the data also reveal heterogeneities of structure, subtleties of chemical interactions, and apparent inconsistencies between diverse data types. As a result, incorporation of all relevant data requires expert choices to combine computational and informatics methods, along with human insight.

Evaluating the predictivity of virtual screening for ABL kinase inhibitors to hinder drug resistance.

Virtual screening methods are now widely used in early stages of drug discovery, aiming to rank potential inhibitors. However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space for potential new compounds. In this study, we have taken a retrospective approach to evaluate virtual screening methods for the leukemia target kinase ABL1 and its drug-resistant mutant ABL1-T315I.

Structural origins of AGC protein kinase inhibitor selectivities: PKA as a drug discovery tool.

The era of structure-based protein kinase inhibitor design began in the early 1990s with the determination of crystal structures of protein kinase A (PKA, or cyclic AMP-dependent kinase). Although many other protein kinases have since been extensively characterized, PKA remains a prototype for studies of protein kinase active conformations. It serves well as a model for the structural properties of AGC subfamily protein kinases, clarifying inhibitor selectivity profiles.

1,2,3-triazole analogs of combretastatin A-4 as potential microtubule-binding agents.

A series of cis-restricted 1,4- and 1,5-disubstituted 1,2,3-triazole analogs of combretastatin A-4 (1) have been prepared. Cytotoxicity and tubulin inhibition studies showed that 2-methoxy-5-((5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)aniline (5e) and 2-methoxy-5-(1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-5-yl)aniline (6e) were two of the most active compounds. Molecular modeling studies revealed that the N-2 and N-3 atoms in the triazole rings in 5e and 6e did not form hydrogen bonds with the amino acids in the anticipated pharmacophore.

Protein kinase inhibition of clinically important staurosporine analogues.

The isolation in 1977 of the microbial alkaloid staurosporine inaugurated research into several distinct series of related natural and synthetic compounds. This has especially included research into applications as anticancer drugs, beginning with the observation of low nanomolar inhibition of protein kinases. At present, several staurosporine cognates are in advanced clinical trials as anticancer agents, with the potential to join the 10 other protein kinase inhibitors now approved for clinical use.

Ligand-induced stabilization and activation of peroxisome proliferator-activated receptor gamma.

Peroxisome proliferator-activated receptor gamma belongs to the nuclear receptor superfamily and is activated by the antidiabetic drugs rosiglitazone and pioglitazone. Ligand-independent constitutive activity of peroxisome proliferator-activated receptor gamma is also demonstrated. X-ray crystallographic structures show that the active or inactive conformations of the receptor are determined by the position of helix 12 in the C-terminal end.

Molecular recognition of docosahexaenoic acid by peroxisome proliferator-activated receptors and retinoid-X receptor alpha.

The family of peroxisome proliferator-activated receptors (PPARs) is the molecular target of synthetic antidiabetic and hypolipidemic drugs. The side effects of these drugs are limiting their use in patients with high lipid levels. Natural compounds, like Docosahexaenoic acid (DHA) from fish oil, have beneficial effects in the treatment of metabolic diseases, and several DHA derivatives are known to activate PPAR genes.

1,5-Disubstituted 1,2,3-triazoles as cis-restricted analogues of combretastatin A-4: Synthesis, molecular modeling and evaluation as cytotoxic agents and inhibitors of tubulin.

A series of cis-restricted 1,5-disubstituted 1,2,3-triazole analogues of combretastatin A-4 (1) have been prepared. The triazole 12f, 2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline, displayed potent cytotoxic activity against several cancer cell lines with IC(50) values in the nanomolar range. The ability of triazoles to inhibit tubulin polymerization has been evaluated, and 12f inhibited tubulin polymerization with IC(50)=4.

Are fish oil omega-3 long-chain fatty acids and their derivatives peroxisome proliferator-activated receptor agonists?

Background: Peroxisome proliferator-activated receptors (PPARalpha, PPARgamma, and PPARdelta) are physiological sensors for glucose and lipid homeostasis. They are also the targets of synthetic drugs; such as fibrates as PPARalpha agonists which lower lipid level, and glitazones as PPARgamma agonists which lower glucose level. As diabetes and metabolic diseases are often associated with high blood glucose and lipid levels, drugs that activate both PPARalpha/gamma would be a logical approach.

Theoretical calculations of the catalytic triad in short-chain alcohol dehydrogenases/reductases.

Three highly conserved active site residues (Ser, Tyr, and Lys) of the family of short-chain alcohol dehydrogenases/reductases (SDRs) were demonstrated to be essential for catalytic activity and have been denoted the catalytic triad of SDRs. In this study computational methods were adopted to study the ionization properties of these amino acids in SDRs from Drosophila melanogaster and Drosophila lebanonensis. Three enzyme models, with different ionization scenarios of the catalytic triad that might be possible when inhibitors bind to the enzyme cofactor complex, were constructed.

Signposts of docking and scoring in drug design.

Docking and scoring tools are often used in the early stages of drug discovery projects today. Because the language of this field of drug design often includes intermingled terms of physics, chemistry, biology, and medicine, the significant developments of docking and scoring are challenging to follow for non-experts. In this Science Philosophy article, I attempt to clarify the concepts used in docking and scoring to help articulate the successes and limitations of this multidisciplinary field in more comprehensible manner.