6 research outputs found
MM-GBSA and MM-PBSA performance in activity evaluation of AMPA receptor positive allosteric modulators
MM-GBSA and MM-PBSA performance in activity evaluation of AMPA receptor positive allosteric modulator
Influence of Descriptor Implementation on Compound Ranking Based on Multiparameter Assessment
Most of the common
molecular descriptors have numerous different
implementations. This can influence the results of compound prioritization
based on the multiparameter assessment (MPA) approach that allows
a medicinal chemist to simultaneously analyze and achieve the desired
balance of the diverse and often conflicting molecular and pharmacological
properties. In this study, we analyzed the feasibility of using different
implementations of common descriptors (logP, logS, TPSA, logBB, hERG,
nHBA) interchangeably in predesigned sets of requirements in the course
of multiparameter compound optimization. The influence of methods
of descriptor calculation, continuity or discreteness of their values,
their applicability domains, as well as of the nature of desirability
functions in an MPA profile were examined in terms of the stability
of MPA compound ranking. It was shown that the interchangeable use
of different methods of descriptor calculation is reliably acceptable
only for continuously distributed parameters transformed by a smooth
desirability function. If a descriptor in an MPA scheme is discretely
distributed, only the implementation that was used for building the
scoring profile may be used for assessment. An inconsistency of assessment
due to different applicability domains of descriptors was also demonstrated
Influence of Descriptor Implementation on Compound Ranking Based on Multiparameter Assessment
Most of the common
molecular descriptors have numerous different
implementations. This can influence the results of compound prioritization
based on the multiparameter assessment (MPA) approach that allows
a medicinal chemist to simultaneously analyze and achieve the desired
balance of the diverse and often conflicting molecular and pharmacological
properties. In this study, we analyzed the feasibility of using different
implementations of common descriptors (logP, logS, TPSA, logBB, hERG,
nHBA) interchangeably in predesigned sets of requirements in the course
of multiparameter compound optimization. The influence of methods
of descriptor calculation, continuity or discreteness of their values,
their applicability domains, as well as of the nature of desirability
functions in an MPA profile were examined in terms of the stability
of MPA compound ranking. It was shown that the interchangeable use
of different methods of descriptor calculation is reliably acceptable
only for continuously distributed parameters transformed by a smooth
desirability function. If a descriptor in an MPA scheme is discretely
distributed, only the implementation that was used for building the
scoring profile may be used for assessment. An inconsistency of assessment
due to different applicability domains of descriptors was also demonstrated
Influence of Descriptor Implementation on Compound Ranking Based on Multiparameter Assessment
Most of the common
molecular descriptors have numerous different
implementations. This can influence the results of compound prioritization
based on the multiparameter assessment (MPA) approach that allows
a medicinal chemist to simultaneously analyze and achieve the desired
balance of the diverse and often conflicting molecular and pharmacological
properties. In this study, we analyzed the feasibility of using different
implementations of common descriptors (logP, logS, TPSA, logBB, hERG,
nHBA) interchangeably in predesigned sets of requirements in the course
of multiparameter compound optimization. The influence of methods
of descriptor calculation, continuity or discreteness of their values,
their applicability domains, as well as of the nature of desirability
functions in an MPA profile were examined in terms of the stability
of MPA compound ranking. It was shown that the interchangeable use
of different methods of descriptor calculation is reliably acceptable
only for continuously distributed parameters transformed by a smooth
desirability function. If a descriptor in an MPA scheme is discretely
distributed, only the implementation that was used for building the
scoring profile may be used for assessment. An inconsistency of assessment
due to different applicability domains of descriptors was also demonstrated
Influence of Descriptor Implementation on Compound Ranking Based on Multiparameter Assessment
Most of the common
molecular descriptors have numerous different
implementations. This can influence the results of compound prioritization
based on the multiparameter assessment (MPA) approach that allows
a medicinal chemist to simultaneously analyze and achieve the desired
balance of the diverse and often conflicting molecular and pharmacological
properties. In this study, we analyzed the feasibility of using different
implementations of common descriptors (logP, logS, TPSA, logBB, hERG,
nHBA) interchangeably in predesigned sets of requirements in the course
of multiparameter compound optimization. The influence of methods
of descriptor calculation, continuity or discreteness of their values,
their applicability domains, as well as of the nature of desirability
functions in an MPA profile were examined in terms of the stability
of MPA compound ranking. It was shown that the interchangeable use
of different methods of descriptor calculation is reliably acceptable
only for continuously distributed parameters transformed by a smooth
desirability function. If a descriptor in an MPA scheme is discretely
distributed, only the implementation that was used for building the
scoring profile may be used for assessment. An inconsistency of assessment
due to different applicability domains of descriptors was also demonstrated
Inhibitors of Tick-Borne Flavivirus Reproduction from Structure-Based Virtual Screening
Flaviviruses
form a large family of enveloped viruses affecting
millions of people over the world. To date, no specific therapy was
suggested for the infected people, making the treatment exclusively
symptomatic. Several attempts were performed earlier for the design
of fusion inhibitors for mosquito-borne flaviviruses, whereas for
the tick-borne flaviviruses such design had not been performed. We
have constructed homology models of envelope glycoproteins of tick-transmitted
flaviviruses with the detergent binding pocket in the open state.
Molecular docking of substituted 1,4-dihydropyridines and pyrido[2,1-<i>b</i>][1,3,5]thiadiazines was made against these models, and
89 hits were selected for the in vitro experimental evaluation. Seventeen
compounds showed significant inhibition against tick-borne encephalitis
virus, Powassan virus, or Omsk hemorrhagic fever virus in the 50%
plaque reduction test in PEK cells. These compounds identified through
rational design are the first ones possessing reproduction inhibition
activity against tick-borne flaviviruses