9 research outputs found
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Macrocycle Conformational Sampling with MacroModel
Sampling low energy conformations
of macrocycles is challenging
due to the large size of many of these molecules and the constraints
imposed by the macrocycle. We present a new conformational search
method (implemented in MacroModel) that uses brief MD simulations
followed by minimization and normal-mode search steps. The method
was parametrized using a set of 100 macrocycles from the PDB and CSD.
It was then tested on a publicly available data set for which there
are published results using alternative methods; we found that when
the same force field is used (in this case MMFFs in vacuum), our method
tended to identify conformations with lower energies than what the
other methods identified. The performance on a new set of 50 macrocycles
from the PDB and CSD was also quite good; the mean and median RMSD
values for just the ring atoms were 0.60 and 0.33 Ã…, respectively.
However, the RMSD values for macrocycles with more than 30 ring-atoms
were quite a bit larger compared to the smaller macrocycles. Possible
origins for this and ideas for improving the performance on very large
macrocycles are discussed
Improving Accuracy, Diversity, and Speed with Prime Macrocycle Conformational Sampling
A novel method for
exploring macrocycle conformational space, Prime
macrocycle conformational sampling (Prime-MCS), is introduced and
evaluated in the context of other available algorithms (Molecular
Dynamics, LowModeMD in MOE, and MacroModel Baseline Search). The algorithms
were benchmarked on a data set of 208 macrocycles which was curated
for diversity from the Cambridge Structural Database, the Protein
Data Bank, and the Biologically Interesting Molecule Reference Dictionary.
The algorithms were evaluated in terms of accuracy (ability to reproduce
the crystal structure), diversity (coverage of conformational space),
and computational speed. Prime-MCS most reliably reproduced crystallographic
structures for RMSD thresholds >1.0 Ã…, most often produced
the
most diverse conformational ensemble, and was most often the fastest
algorithm. Detailed analysis and examination of both typical and outlier
cases were performed to reveal characteristics, shortcomings, expected
performance, and complementarity of the methods
Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors
On the basis of a crystal structure
of a phenylpyrrolidine lead and subsequent molecular modeling results,
we designed and synthesized a novel series of macrocyclic FVIIa inhibitors.
The optimal 16-membered macrocycle was 60-fold more potent than an
acyclic analog. Further potency optimization by incorporation of P1′
alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa <i>K</i><sub>i</sub> = 1.6 nM, excellent selectivity against a
panel of seven serine proteases, and FVII-deficient prothrombin time
EC<sub>2<i>x</i></sub> = 1.2 μM. Discovery of this
potent, selective macrocyclic scaffold opens new possibilities for
the development of orally bioavailable FVIIa inhibitors
Atropisomer Control in Macrocyclic Factor VIIa Inhibitors
Incorporation of a methyl group onto
a macrocyclic FVIIa inhibitor
improves potency 10-fold but is accompanied by atropisomerism due
to restricted bond rotation in the macrocyclic structure, as demonstrated
by NMR studies. We designed a conformational constraint favoring the
desired atropisomer in which this methyl group interacts with the
S2 pocket of FVIIa. A macrocyclic inhibitor incorporating this constraint
was prepared and demonstrated by NMR to reside predominantly in the
desired conformation. This modification improved potency 180-fold
relative to the unsubstituted, racemic macrocycle and improved selectivity.
An X-ray crystal structure of a closely related analogue in the FVIIa
active site was obtained and matches the NMR and modeled conformations,
confirming that this conformational constraint does indeed direct
the methyl group into the S2 pocket as designed. The resulting rationally
designed, conformationally stable template enables further optimization
of these macrocyclic inhibitors
Design and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors
Two
novel series of meta-linked phenylglycine-based macrocyclic
FVIIa inhibitors have been designed to improve the rodent metabolic
stability and PK observed with the precursor para-linked phenylglycine
macrocycles. Through iterative structure-based design and optimization,
the TF/FVIIa <i>K</i><sub>i</sub> was improved to subnanomolar
levels with good clotting activity, metabolic stability, and permeability
Discovery of Novel P1 Groups for Coagulation Factor VIIa Inhibition Using Fragment-Based Screening
A multidisciplinary,
fragment-based screening approach involving
protein ensemble docking and biochemical and NMR assays is described.
This approach led to the discovery of several structurally diverse,
neutral surrogates for cationic factor VIIa P1 groups, which are generally
associated with poor pharmacokinetic (PK) properties. Among the novel
factor VIIa inhibitory fragments identified were aryl halides, lactams,
and heterocycles. Crystallographic structures for several bound fragments
were obtained, leading to the successful design of a potent factor
VIIa inhibitor with a neutral lactam P1 and improved permeability
Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa–Tissue Factor Complex
Inhibitors of the tissue factor (TF)/factor
VIIa complex (TF-FVIIa)
are promising novel anticoagulants which show excellent efficacy and
minimal bleeding in preclinical models. Starting with an aminoisoquinoline
P1-based macrocyclic inhibitor, optimization of the P′ groups
led to a series of highly potent and selective TF-FVIIa inhibitors
which displayed poor permeability. Fluorination of the aminoisoquinoline
reduced the basicity of the P1 group and significantly improved permeability.
The resulting lead compound was highly potent, selective, and achieved
good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated
robust antithrombotic activity in a rabbit model of arterial thrombosis
Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors
Inhibitors
of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising
novel anticoagulants that show excellent efficacy and minimal bleeding
in preclinical models. On the basis of a zwitterionic phenylglycine
acylsulfonamide <b>1</b>, a phenylglycine benzylamide <b>2</b> was shown to possess improved permeability and oral bioavailability.
Optimization of the benzylamide, guided by X-ray crystallography,
led to a potent TF-FVIIa inhibitor <b>18i</b> with promising
oral bioavailability, but promiscuous activity in an in vitro safety
panel of receptors and enzymes. Introducing an acid on the pyrrolidine
ring, guided by molecular modeling, resulted in highly potent, selective,
and efficacious TF-FVIIa inhibitors with clean in vitro safety profile.
The pyrrolidine acid <b>20</b> showed a moderate clearance,
low volume of distribution, and a short <i>t</i><sub>1/2</sub> in dog PK studies