33 research outputs found
A community effort in SARS-CoV-2 drug discovery.
peer reviewedThe COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against Covid-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments.R-AGR-3826 - COVID19-14715687-CovScreen (01/06/2020 - 31/01/2021) - GLAAB Enric
Thumbs Down for HIV: Domain Level Rearrangements Do Occur in the NNRTI-Bound HIVâ1 Reverse Transcriptase
One of the principal targets in human immunodeficiency
virus type
1 (HIV-1) therapy is the reverse transcriptase (RT) enzyme. Non-nucleoside
RT inhibitors (NNRTIs) are a class of highly specific drugs which
bind to a pocket approximately 10 Ă
from the polymerase active
site, inhibiting the enzyme allosterically. It is widely believed
that NNRTIs function as âmolecular wedgesâ, disrupting
the region between thumb and palm subdomains of the p66 subunit and
locking the thumb in a wide-open conformation. Crystal structure data
suggest that the binding of NNRTIs forces RT into a wide-open conformation
in which the separation between the thumb and fingers subdomains is
much higher than in the apo structure. Using ensemble molecular dynamics
simulations (aggregate sampling âŒ600 ns), we have captured
RT bound to the NNRTI efavirenz in a closed conformation similar to
that of the apo enzyme, suggesting the constraint of thumb motion
is not as complete as previously believed. Rather, our investigation
confirms that a conformational distribution across open and closed
states must exist in the drug-bound enzyme and that allosteric modulation
is effected via the alteration of the kinetic landscape of conformational
transitions upon drug-binding. A more detailed understanding of the
mechanism of NNRTI inhibition and the effect of binding upon domain
motion could aid the design of more effective inhibitors and help
identify novel allosteric sites
Thumbs Down for HIV: Domain Level Rearrangements Do Occur in the NNRTI-Bound HIVâ1 Reverse Transcriptase
One of the principal targets in human immunodeficiency
virus type
1 (HIV-1) therapy is the reverse transcriptase (RT) enzyme. Non-nucleoside
RT inhibitors (NNRTIs) are a class of highly specific drugs which
bind to a pocket approximately 10 Ă
from the polymerase active
site, inhibiting the enzyme allosterically. It is widely believed
that NNRTIs function as âmolecular wedgesâ, disrupting
the region between thumb and palm subdomains of the p66 subunit and
locking the thumb in a wide-open conformation. Crystal structure data
suggest that the binding of NNRTIs forces RT into a wide-open conformation
in which the separation between the thumb and fingers subdomains is
much higher than in the apo structure. Using ensemble molecular dynamics
simulations (aggregate sampling âŒ600 ns), we have captured
RT bound to the NNRTI efavirenz in a closed conformation similar to
that of the apo enzyme, suggesting the constraint of thumb motion
is not as complete as previously believed. Rather, our investigation
confirms that a conformational distribution across open and closed
states must exist in the drug-bound enzyme and that allosteric modulation
is effected via the alteration of the kinetic landscape of conformational
transitions upon drug-binding. A more detailed understanding of the
mechanism of NNRTI inhibition and the effect of binding upon domain
motion could aid the design of more effective inhibitors and help
identify novel allosteric sites
Rapid Conformational Fluctuations of Disordered HIVâ1 Fusion Peptide in Solution
The
conformationally flexible fusion peptide (FP) of HIV-1 is indispensible
for viral infection of host cells, due to its ability to insert into
and tightly couple with phospholipid membranes. There are conflicting
reports on the membrane-associated structure of FP, and solution structure
information is limited, yet such a structure is the target for a novel
class of antiretroviral inhibitors. An ensemble of explicit solvent
molecular dynamics simulations, initiated from a disordered HIV-1
FP (aggregate time of âŒ30 ÎŒs), revealed that while the
vast majority of conformations predominantly lack secondary structure,
both spontaneous formation and rapid interconversion of local secondary
structure elements occur, highlighting the structural plasticity of
the peptide. Therefore, even at this rapid time scale, FP constitutes
a diverse and flexible conformational ensemble in solution. Secondary
structure clustering reveals that the most prominent ordered elements
are α- and 3â10-helical subsets of membrane-bound conformations,
while trace populations within 2 Ă
RMSD of all complete membrane-bound
conformations are found to pre-exist in the solution ensemble. Since
inhibitor bound conformations of FP are only rarely found, FP inhibitors
could function by modulating the conformational ensemble and binding
to nonfusogenic FP structures. A thermodynamic characterization of
the most prominent ordered nonfusogenic structures could facilitate
the future design of improved FP inhibitors