5 research outputs found
A Machine Learning Approach for Predicting HIV Reverse Transcriptase Mutation Susceptibility of Biologically Active Compounds
HIV resistance emerging against antiretroviral
drugs represents
a great threat to the continued prolongation of the lifespans of HIV-infected
patients. Therefore, methods capable of predicting resistance susceptibility
in the development of compounds are in great need. By targeting the
major reverse transcription residues Y181, K103, and L100, we used
the biological activities of compounds against these enzymes and the
wild-type reverse transcriptase to create Naïve Bayes Networks.
Through this machine learning approach, we could predict, with high
accuracy, whether a compound would be susceptible to a loss of potency
due to resistance. Also, we could perfectly predict retrospectively
whether compounds would be susceptible to both a K103 mutant RT and
a Y181 mutant RT. In the study presented here, our method outperformed
a traditional molecular mechanics approach. This method should be
of broad interest beyond drug discovery efforts, and serves to expand
the utility of machine learning for the prediction of physical, chemical,
or biological properties using the vast information available in the
literature
A Machine Learning Approach for Predicting HIV Reverse Transcriptase Mutation Susceptibility of Biologically Active Compounds
HIV resistance emerging against antiretroviral
drugs represents
a great threat to the continued prolongation of the lifespans of HIV-infected
patients. Therefore, methods capable of predicting resistance susceptibility
in the development of compounds are in great need. By targeting the
major reverse transcription residues Y181, K103, and L100, we used
the biological activities of compounds against these enzymes and the
wild-type reverse transcriptase to create Naïve Bayes Networks.
Through this machine learning approach, we could predict, with high
accuracy, whether a compound would be susceptible to a loss of potency
due to resistance. Also, we could perfectly predict retrospectively
whether compounds would be susceptible to both a K103 mutant RT and
a Y181 mutant RT. In the study presented here, our method outperformed
a traditional molecular mechanics approach. This method should be
of broad interest beyond drug discovery efforts, and serves to expand
the utility of machine learning for the prediction of physical, chemical,
or biological properties using the vast information available in the
literature
Novel Cyclopropyl-Indole Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors
The HIV pandemic represents one of the most serious diseases
to
face mankind in both a social and economic context, with many developing
nations being the worst afflicted. Due to ongoing resistance issues
associated with the disease, the design and synthesis of anti-HIV
agents presents a constant challenge for medicinal chemists. Utilizing
molecular modeling, we have designed a series of novel cyclopropyl
indole derivatives as HIV non-nucleoside reverse transcriptase inhibitors
and carried out their preparation. These compounds facilitate a double
hydrogen bonding interaction to Lys101 and efficiently occupy the
hydrophobic pockets in the regions of Tyr181/188 and Val179. Several
of these compounds inhibited HIV replication as effectively as nevirapine
when tested in a phenotypic assay
Novel Microtubule-Targeting 7‑Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities
Docking studies of tubulin-targeting
C2-substituted 7-deazahypoxanthine
analogues of marine alkaloid rigidins led to the design and synthesis
of compounds containing linear C2-substituents. The C2-alkynyl analogue
was found to have double- to single-digit nanomolar antiproliferative
IC<sub>50</sub> values and showed statistically significant tumor
size reduction in a colon cancer mouse model at nontoxic concentrations.
These results provide impetus and further guidance for the development
of these rigidin analogues as anticancer agents
Design and Optimization of Novel Competitive, Non-peptidic, SARS-CoV‑2 M<sup>pro</sup> Inhibitors
The SARS-CoV-2 main protease (Mpro) has been
proven
to be a highly effective target for therapeutic intervention, yet
only one drug currently holds FDA approval status for this target.
We were inspired by a series of publications emanating from the Jorgensen
and Anderson groups describing the design of potent, non-peptidic,
competitive SARS-CoV-2 Mpro inhibitors, and we saw an opportunity
to make several design modifications to improve the overall pharmacokinetic
profile of these compounds without losing potency. To this end, we
created a focused virtual library using reaction-based enumeration
tools in the Schrödinger suite. These compounds were docked
into the Mpro active site and subsequently prioritized
for synthesis based upon relative binding affinity values calculated
by FEP+. Fourteen compounds were selected, synthesized, and evaluated
both biochemically and in cell culture. Several of the synthesized
compounds proved to be potent, competitive Mpro inhibitors
with improved metabolic stability profiles