A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors

Abstract

Molecular simulations led to the discovery of a new class of small molecules that inhibit the cyclophilin family of proteins.

Dynamic design: manipulation of millisecond timescale motions on the energy landscape of Cyclophilin A

“…Our results open an exciting opportunity for determining this in silico as part of rational drug design endeavours. In the specific case of CypA, current treatments methods have insufficient isoform selectivity 53,54 . We envision that aMD/MSM can be used to selectively target transient states that are differently populated among different protein isoforms, hence paving the way for the rational drug design of isoform selective inhibitors.…”

“…We test the novel aMD/MSM protocol by both characterising and rationally modifying the free energy surface of human cyclophilin A (CypA). This enzyme is a human prolyl isomerase whose incorporation into new virus assemblies is essential for HIV-1 infectivity [45][46][47][48] and HCV replication 49 , making it a major drug target [50][51][52][53][54][55][56][57] . This protein has been widely studied [58][59][60][61][62][63][64][65][66][67] To manipulate the energy surface, we implemented a design strategy based on hydrogen bonding patterns to stabilise specifically sparsely populated conformers with millisecond lifetimes (Fig.…”

Assessment of Binding Affinity via Alchemical Free-Energy Calculations

“…[1][2][3] Such calculations have been applied to predict ligand binding affinities of large datasets, yielding on average predictions accurate to within 0.8 kcal/mol, thus adding significant value to drug discovery projects . [4][5][6][7] However, lack of automation is still a major obstacle to a more routine application of these methods, despite several tools to address this being in development. [8][9][10][11] Furthermore, carrying out alchemical free energy calculations requires expert knowledge, since assessing the quality and validity of these simulations can be non-trivial.…”

“…12,33,34 The SOMD package available within the Sire framework has been successfully applied to relative and absolute binding free energy studies of a range of fragments, drug-like small molecules, carbohydrates, host-guest systems. [5][6][7]30,[35][36][37][38] However, a systematic comparison on standard datasets has not been published to date. Here we report a large-scale validation of Flare's FEP implementation on the Wang et al 1 dataset, as well as on a smaller dataset of more challenging scaffold hopping modifications .…”

A Hybrid Alchemical Free Energy and Machine Learning Methodology for the Calculation of Absolute Hydration Free Energies of Small Molecules

“…Alchemical free energy calculations (or Free Energy Perturbation -FEP-) are increasingly used in academia and industry to support ligand optimisation problems in the early stage of drug discovery. [1][2][3][4] The domain of applicability of current alchemical methodologies has to date mainly been restricted to hit-to-lead and lead optimisation scenarios owing to limitations in computing cost, conformational sampling, and the accuracy of the potential energy functions used to compute protein-ligand energetics. [5][6][7][8][9][10] There is continued interest in the development of more accurate potential energy functions to benchmark FEP workflows on diverse well curated diverse protein-ligand datasets, [11][12][13][14] and for applications to blinded challenges or methodological studies.…”