Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors.

The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound by modifying the heteroaryl C-H hinge and linker regions.

Augmenting Hit Identification by Virtual Screening Techniques in Small Molecule Drug Discovery.

Two orthogonal approaches for hit identification in drug discovery are large-scale and screening. In recent years, due to the emergence of new targets and a rapid increase in the size of the readily synthesizable chemical space, there is a growing emphasis on the integration of the two techniques to improve the hit finding efficiency. Here, we highlight three examples of drug discovery projects at Merck & Co.

Molecular Dynamics Simulations of a Conformationally Mobile Peptide-Based Catalyst for Atroposelective Bromination.

It is widely accepted that structural rigidity is required to achieve high levels of asymmetric induction in catalytic, enantioselective reactions. This fundamental design principle often does not apply to highly selective catalytic peptides that often exhibit conformational heterogeneity. As a result, these complex systems are particularly challenging to study both experimentally and computationally.

Improved Description of Sulfur Charge Anisotropy in OPLS Force Fields: Model Development and Parameterization.

The atomic point-charge model used in most molecular mechanics force fields does not represent well the electronic anisotropy that is featured in many directional noncovalent interactions. Sulfur participates in several types of such interactions with its lone pairs and σ-holes. The current study develops a new model, via the addition of off-atom charged sites, for a variety of sulfur compounds in the OPLS-AA and OPLS/CM5 force fields to address the lack of charge anisotropy.

Hydration Properties and Solvent Effects for All-Atom Solutes in Polarizable Coarse-Grained Water.

Due to the importance of water in chemical and biological systems, a coarse-grained representation of the solvent can greatly simplify the description of the system while retaining key thermodynamic properties of the medium. A multiscale solvation model that couples all-atom solutes and polarizable Martini coarse-grained water (AAX/CGS) is developed to reproduce free energies of hydration of organic solutes. Using Monte Carlo/free energy perturbation (MC/FEP) calculations, results from multiscale and all-atom simulations are compared.

Cooperative effects and optimal halogen bonding motifs for self-assembling systems.

Halogen bonding, due to its directionality and tunable strength, is being increasingly utilized in self-assembling materials and crystal engineering. Using density functional theory (DFT) and molecular mechanics (OPLS/CM1Ax) calculations, multiply halogen bonded complexes of brominated imidazole and pyridine are investigated along with their potential in construction of self-assembling architectures. Dimers with 1-10 halogen bonds are considered and reveal maximal binding energies of 3-36 kcal/mol.