The reorganization energy of compounds upon binding to proteins, from dynamic and solvated bound and unbound states.

The intramolecular reorganization energy (ΔE) of compounds upon binding to proteins is a component of the binding free energy, which has long received particular attention, for fundamental and practical reasons. Understanding ΔE would benefit the science of molecular recognition and drug design. For instance, the tolerable strain energy of compounds upon binding has been elusive.

Design and Synthesis of Pyrrolo[2,3-]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate.

Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-]pyrimidines underwent optimization using X-ray structures of LRRK2 kinase domain surrogates, based on checkpoint kinase 1 (CHK1) and a CHK1 10-point mutant. (2)-2-Methylpyrrolidin-1-yl derivative (LRRK2 G2019S c 0.

Modelling the binding mode of macrocycles: Docking and conformational sampling.

Drug discovery is increasingly tackling challenging protein binding sites regarding molecular recognition and druggability, including shallow and solvent-exposed protein-protein interaction interfaces. Macrocycles are emerging as promising chemotypes to modulate such sites. Despite their chemical complexity, macrocycles comprise important drugs and offer advantages compared to non-cyclic analogs, hence the recent impetus in the medicinal chemistry of macrocycles.

Energy windows for computed compound conformers: covering artefacts or truly large reorganization energies?

The generation of 3D conformers of small molecules underpins most computational drug discovery. Thus, the conformer quality is critical and depends on their energetics. A key parameter is the empirical conformational energy window (ΔE), since only conformers within ΔE are retained.

Using Spin-Coated Silver Nanoparticles/Zinc Oxide Thin Films to Improve the Efficiency of GaInP/(In)GaAs/Ge Solar Cells.

We synthesized a silver nanoparticle/zinc oxide (Ag NP/ZnO) thin film by using spin-coating technology. The treatment solution for Ag NP/ZnO thin film deposition contained zinc acetate (Zn(CH₃COO)₂), sodium hydroxide (NaOH), and silver nitrate (AgNO₃) aqueous solutions. The crystalline characteristics, surface morphology, content of elements, and reflectivity of the Ag NPs/ZnO thin film at various concentrations of the AgNO₃ aqueous solution were investigated using X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, atomic force microscopy, and ultraviolet⁻visible⁻near infrared spectrophotometry.

Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1).

Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity.

The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors.

Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1 (MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was identified.

Towards understanding the unbound state of drug compounds: Implications for the intramolecular reorganization energy upon binding.

There has been an explosion of structural information for pharmaceutical compounds bound to biological targets, but the conformations and dynamics of compounds free in solution are poorly characterized, if at all. Yet, knowledge of the unbound state is essential to understand the fundamentals of molecular recognition, including the much debated conformational intramolecular reorganization energy of a compound upon binding (ΔEReorg). Also, dependable observation of the unbound compounds is important for ligand-based drug discovery, e.

Tackling the conformational sampling of larger flexible compounds and macrocycles in pharmacology and drug discovery.

Computational conformational sampling underpins much of molecular modeling and design in pharmaceutical work. The sampling of smaller drug-like compounds has been an active area of research. However, few studies have tested in details the sampling of larger more flexible compounds, which are also relevant to drug discovery, including therapeutic peptides, macrocycles, and inhibitors of protein-protein interactions.

Drug-like bioactive structures and conformational coverage with the LigPrep/ConfGen suite: comparison to programs MOE and catalyst.

Computational conformational sampling underpins many aspects of small molecule modeling and design in pharmaceutical work. This work examined in detail the widely distributed LigPrep/ConfGen software suite and the conformational models it produces for drug-like compounds. We also compare LigPrep/ConfGen to MOE and Catalyst.

Conformational sampling and energetics of drug-like molecules.

The pharmacological properties of small organic molecules depend on their three-dimensional (3D) structure. That includes physico-chemical properties (e.g.

Lessons for fragment library design: analysis of output from multiple screening campaigns.

Over the past 8 years, we have developed, refined and applied a fragment based discovery approach to a range of protein targets. Here we report computational analyses of various aspects of our fragment library and the results obtained for fragment screening. We reinforce the finding of others that the experimentally observed hit rate for screening fragments can be related to a computationally defined druggability index for the target.

Conformational sampling of druglike molecules with MOE and catalyst: implications for pharmacophore modeling and virtual screening.

Computational conformational sampling is integral to small molecule pharmaceutical research, for detailed conformational analysis and high-throughput 3D library enumeration. These two regimes were tested in details for the general-purpose modeling program MOE, using its three conformational sampling methods, i.e.

Chemical substituent effect on pyridine permeability and mechanistic insight from computational molecular descriptors.

The objective was (1) to evaluate the chemical substituent effect on Caco-2 permeability, using a congeneric series of pyridines, and (2) compare molecular descriptors from a computational chemistry approach against molecular descriptors from the Hansch approach for their abilities to explain the chemical substituent effect on pyridine permeability. The passive permeability of parent pyridine and 14 monosubstituted pyridines were measured across Caco-2 monolayers. Computational chemistry analysis was used to obtain the following molecular descriptions: solvation free energies, solvent accessible surface area, polar surface area, and cavitation energy.

A structure-based strategy to identify new molecular scaffolds targeting the bacterial ribosomal A-site.

The need for novel antibiotics is widely recognized. A well validated target of antibiotics is the bacterial ribosome. Recent X-ray structures of the ribosome bound to antibiotics have shed new light on the binding sites of these antibiotics, providing fresh impetus for structure-based strategies aiming at identifying new ribosomal ligands.

Structure-based inhibitor design targeting HIV-1 integrase.

HIV integrase (IN) is a viral-encoded protein that catalyzes the breaking and joining reactions that mediate integration of viral DNA into the host genome. Therefore, IN offers a unique target for the development of novel anti-HIV and anti-AIDS therapeutics. To take advantage of this potential, drug discovery efforts via structure-based design approaches have been undertaken.

Combined ab initio/empirical approach for optimization of Lennard-Jones parameters for polar-neutral compounds.

The study of small functionalized organic molecules in aqueous solution is a useful step toward gaining a basic understanding of the behavior of biomolecular systems in their native aqueous environment. Interest in studying amines and fluorine-substituted compounds has risen from their intrinsic physicochemical properties and their prevalence in biological and pharmaceutical compounds. In the present study, a previously developed approach which optimizes Lennard-Jones (LJ) parameters via the use of rare gas atoms combined with the reproduction of experimental condensed phase properties was extended to polar-neutral compounds.