Benchmark of Generic Shapes for Macrocycles

Abstract

Macrocycles target proteins that are otherwise considered undruggable because of a lack of hydrophobic cavities and the presence of extended featureless surfaces. Increasing efforts by computational chemists have developed effective software to overcome the restrictions of torsional and conformational freedom that arise as a consequence of macrocyclization. Moloc is an efficient algorithm, with an emphasis on high interactivity, and has been constantly updated since 1986 by drug designers and crystallographers of the Roche biostructural community. In this work, we have benchmarked the shape-guided algorithm using a dataset of 208 macrocycles, carefully selected on the basis of structural complexity. We have quantified the accuracy, diversity, speed, exhaustiveness, and sampling efficiency in an automated fashion and we compared them with four commercial (Prime, MacroModel, molecular operating environment, and molecular dynamics) and four open-access (experimental-torsion distance geometry with additional “basic knowledge” alone and with Merck molecular force field minimization or universal force field minimization, Cambridge Crystallographic Data Centre conformer generator, and conformator) packages. With three-quarters of the database processed below the threshold of high ring accuracy, Moloc was identified as having the highest sampling efficiency and exhaustiveness without producing thousands of conformations, random ring splitting into two half-loops, and possibility to interactively produce globular or flat conformations with diversity similar to Prime, MacroModel, and molecular dynamics. The algorithm and the Python scripts for full automatization of these parameters are freely available for academic use.

High-Quality Conformer Generation with CONFORGE: Algorithm and Performance Assessment

“…When it comes to the generation of representative conformer ensembles of macrocyclic structures, algorithms face the challenge of uniformly searching a huge conformational space in an acceptable amount of time whose size increases dramatically with the number of (partially) rotatable bonds in the macrocycle . Recently, several studies were published that benchmarked well-known conformer generators regarding their ability to sample macrocycle conformations with enough accuracy and diversity for common CADD applications. − The methods employed by these programs can be divided into systematic and stochastic approaches. For example, the conformer generators Omega macrocycle, MOE LowModeMD, MacroModel, Balloon, and RDKit ETKDG all pursue a stochastic search strategy.…”

“… 44 Recently, several studies were published that benchmarked well-known conformer generators regarding their ability to sample macrocycle conformations with enough accuracy and diversity for common CADD applications. 45 − 47 The methods employed by these programs can be divided into systematic and stochastic approaches. For example, the conformer generators Omega macrocycle, 48 MOE LowModeMD, 13 MacroModel, 49 Balloon, 21 and RDKit ETKDG 50 all pursue a stochastic search strategy.…”

Dynamic Docking of Macrocycles in Bound and Unbound Protein Structures with DynaDock

“…Different strategies have been developed for tackling this issue, and the number of recent publications on exploration of MC conformational space highlights the relevance of such methods . These include stochastic algorithms, where the MC ring is broken, the linear parts are sampled, and fused back together; , distance geometry, , generic shapes, and knowledge-based algorithms, , as well as inverse kinematics approaches. , Furthermore, deterministic methods can be used for conformational sampling, e.g., performing molecular dynamics (MD) simulations, usually at elevated temperatures, compensating the increased interconversion barrier. − Approaches based on metadynamics for conformer generation (and subsequent docking) have been explored in a case study and more recently investigated in benchmark studies …”

Multicomponent Macrocyclic IL-17a Modifier

“…For this, we created a virtual library of 1000 macrocycles. 24 The chemistry consisted of a mono-acylation of an α,ω-bis primary amine with a cyclic carboxylic acid anhydride. 15 The resulting α,ω-amino carboxylic acid was then subject to an intramolecular Ugi reaction, employing an isocyanide and an oxo component, to yield the highly functionalized macrocycle.…”

“…To test our VS hypothesis in a timely manner, we focused on a recently described (by us) short and convergent two-step macrocycle synthesis (Scheme ). For this, we created a virtual library of 1000 macrocycles . The chemistry consisted of a mono-acylation of an α,ω-bis primary amine with a cyclic carboxylic acid anhydride .…”