Prediction of Threonine-Tyrosine Kinase Receptor-Ligand Unbinding Kinetics with Multiscale Milestoning and Metadynamics.

Accurately describing protein-ligand binding and unbinding kinetics remains challenging. Computational calculations are difficult and costly, while experimental measurements often lack molecular detail and can be unobtainable. Here, we extend our multiscale milestoning method, Simulation-Enabled Estimation of Kinetics Rates (SEEKR), with metadynamics molecular dynamics simulations to yield accurate small molecule drug residence times.

Origin of the kinetic HDAC2-selectivity of an HDAC inhibitor.

A newly synthesized small molecule, KTT-1, exhibits kinetically selective inhibition of histone deacetylase 2, HDAC2, over its homologous enzyme, HDAC1. KTT-1 is hard to be released from the HDAC2/KTT-1 complex, compared to the HDAC1/KTT-1 complex and the residence time of KTT-1 in HDAC2 is longer than that in HDAC1. To explore the physical origin of this kinetic selectivity, we performed replica-exchange umbrella sampling molecular dynamics simulations for formation of both complexes.

Highly Potent and Oral Macrocyclic Peptides as a HIV-1 Protease Inhibitor: mRNA Display-Derived Hit-to-Lead Optimization.

Human immunodeficiency virus type-1 (HIV-1) protease is essential for viral propagation, and its inhibitors are key anti-HIV-1 drug candidates. In this study, we discovered a novel HIV-1 protease inhibitor (compound ) with potent antiviral activity and oral bioavailability using a structure-based drug design approach via X-ray crystal structure analysis and improved metabolic stability, starting from hit macrocyclic peptides identified by mRNA display against HIV-1 protease. We found that the improvement of the proteolytic stability of macrocyclic peptides by introducing a methyl group to the α-position of amino acid is crucial to exhibit strong antiviral activity.

Pocket-to-Lead: Structure-Based Design of Novel Non-peptidic HIV-1 Protease Inhibitors Using the Ligand Binding Pocket as a Template.

A novel strategy for lead identification that we have dubbed the "Pocket-to-Lead" strategy is demonstrated using HIV-1 protease as a model target. Sometimes, it is difficult to obtain hit compounds because of the difficulties in satisfying the complex pharmacophoric features. In this study, a virtual fragment hit which does not match all of the pharmacophore features but has key interactions and vectors that could grow into remaining pharmacophore features was optimized .

Discovery of Extremely Selective Fused Pyridine-Derived β-Site Amyloid Precursor Protein-Cleaving Enzyme (BACE1) Inhibitors with High In Vivo Efficacy through 10s Loop Interactions.

β-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is considered to be a promising target for treating Alzheimer's disease. However, all clinical BACE1 inhibitors have failed due to lack of efficacy, and some have even led to cognitive worsening. Recent evidence points to the importance of avoiding BACE2 inhibition along with careful dose titration.

Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective β-Secretase (BACE1) Inhibitors over BACE2.

BACE1 is an attractive target for disease-modifying treatment of Alzheimer's disease. BACE2, having high homology around the catalytic site, poses a critical challenge to identifying selective BACE1 inhibitors. Recent evidence indicated that BACE2 has various roles in peripheral tissues and the brain, and therefore, the chronic use of nonselective inhibitors may cause side effects derived from BACE2 inhibition.

Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based β-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial.

Accumulation of amyloid β peptides (Aβ) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aβ production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients.

Discovery of an Extremely Potent Thiazine-Based β-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose.

Genetic evidence points to deposition of amyloid-β (Aβ) as a causal factor for Alzheimer's disease. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead , we describe the discovery of a thiazine-based BACE1 inhibitor with robust Aβ reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where achieved sustained Aβ reduction of 80% at trough level.

Structure-Based Design of Selective β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2.

BACE1 inhibitors hold potential as agents in disease-modifying treatment for Alzheimer's disease. BACE2 cleaves the melanocyte protein PMEL in pigment cells of the skin and eye, generating melanin pigments. This role of BACE2 implies that nonselective and chronic inhibition of BACE1 may cause side effects derived from BACE2.

Discovery of Potent and Centrally Active 6-Substituted 5-Fluoro-1,3-dihydro-oxazine β-Secretase (BACE1) Inhibitors via Active Conformation Stabilization.

β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux.

The use of many-body expansions and geometry optimizations in fragment-based methods.

Conspectus Chemists routinely work with complex molecular systems: solutions, biochemical molecules, and amorphous and composite materials provide some typical examples. The questions one often asks are what are the driving forces for a chemical phenomenon? How reasonable are our views of chemical systems in terms of subunits, such as functional groups and individual molecules? How can one quantify the difference in physicochemical properties of functional units found in a different chemical environment? Are various effects on functional units in molecular systems additive? Can they be represented by pairwise potentials? Are there effects that cannot be represented in a simple picture of pairwise interactions? How can we obtain quantitative values for these effects? Many of these questions can be formulated in the language of many-body effects. They quantify the properties of subunits (fragments), referred to as one-body properties, pairwise interactions (two-body properties), couplings of two-body interactions described by three-body properties, and so on.

An Efficient Method to Evaluate Intermolecular Interaction Energies in Large Systems Using Overlapping Multicenter ONIOM and the Fragment Molecular Orbital Method.

We propose an approach based on the overlapping multicenter ONIOM to evaluate intermolecular interaction energies in large systems and demonstrate its accuracy on several representative systems in the complete basis set limit at the MP2 and CCSD(T) level of theory. In the application to the intermolecular interaction energy between insulin dimer and 4'-hydroxyacetanilide at the MP2/CBS level, we use the fragment molecular orbital method for the calculation of the entire complex assigned to the lowest layer in three-layer ONIOM. The developed method is shown to be efficient and accurate in the evaluation of the protein-ligand interaction energies.

Structure-activity relationships of carboline and carbazole derivatives as a novel class of ATP-competitive kinesin spindle protein inhibitors.

The kinesin spindle protein (KSP) is a mitotic kinesin involved in the establishment of a functional bipolar mitotic spindle during cell division. It is considered to be an attractive target for cancer chemotherapy with reduced side effects. Based on natural product scaffold-derived fused indole-based inhibitors and known biphenyl-type KSP inhibitors, various carboline and carbazole derivatives were synthesized and biologically evaluated.