ABSTRACT
The effects of addition of a methyl group to a lead compound on biological activity are examined. A literature analysis of >2000 cases reveals that an activity boost of a factor of 10 or more is found with an 8% frequency, and a 100-fold boost is a 1 in 200 event. Four cases in the latter category are analyzed in depth to elucidate any unusual aspects of the protein-ligand binding, distribution of water molecules, and changes in conformational energetics. The analyses include Monte Carlo/free-energy perturbation (MC/FEP) calculations for methyl replacements in inhibitor series for p38α MAP kinase, ACK1, PTP1B, and thrombin. Methyl substitutions ortho to an aryl ring can be particularly effective at improving activity by inducing a propitious conformational change. The greatest improvements in activity arise from coupling the conformational gain with the burial of the methyl group in a hydrophobic region of the protein.
Subject(s)
Mitogen-Activated Protein Kinase 14/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry , Protein-Tyrosine Kinases/chemistry , Thrombin/chemistry , Amides/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Molecular Dynamics Simulation , Monte Carlo Method , Protein Binding , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Pyrimidines/pharmacology , Pyrrolidinones/pharmacology , Structure-Activity Relationship , Thermodynamics , Thiophenes/pharmacology , Thrombin/antagonists & inhibitors , Thrombin/metabolismABSTRACT
Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase is being pursued with the assistance of free energy perturbation (FEP) calculations to predict relative free energies of binding. Extension of azole-containing inhibitors into an 'eastern' channel between Phe227 and Pro236 has led to the discovery of potent and structurally novel derivatives.
Subject(s)
Azoles/pharmacology , HIV-1/enzymology , Reverse Transcriptase Inhibitors/pharmacology , Azoles/chemistry , Models, Molecular , Reverse Transcriptase Inhibitors/chemistryABSTRACT
An outbreak among homeless shelter users of a communicable disease with a short generation time would pose serious public health challenges. Data from Toronto were used to examine the number of shelter residents potentially exposed in the event of such an outbreak. A shelter user had contact with a mean of 97 other residents (range, 1-292) in one day and a mean of 120 (range, 2-624) in eight days. After a single week, contact tracing becomes difficult due to the challenge of locating homeless people who have left the shelter system. Over an 8-day period, individuals who used more than one shelter had contact with an average of 98 more other shelter residents than those who stayed in a single shelter had. At the onset of a serious outbreak, it may be desirable to institute policies that strongly encourage individuals to remain at their current shelter for the duration of the outbreak.
Subject(s)
Communicable Diseases/epidemiology , Contact Tracing/statistics & numerical data , Ill-Housed Persons , Adult , Canada , Communicable Disease Control , Disease Outbreaks , Female , Humans , MaleABSTRACT
Efficient optimization of an inactive 2-anilinyl-5-benzyloxadiazole core has been guided by free energy perturbation (FEP) calculations to provide potent non-nucleoside inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (NNRTIs). An FEP "chlorine scan" was performed to identify the most promising sites for substitution of aryl hydrogens. This yielded NNRTIs 8 and 10 with activities (EC50) of 820 and 310 nM for protection of human T-cells from infection by wild-type HIV-1. FEP calculations for additional substituent modifications and change of the core heterocycle readily led to oxazoles 28 and 29, which were confirmed as highly potent anti-HIV agents with activities in the 10-20 nM range. The designed compounds were also monitored for possession of desirable pharmacological properties by use of additional computational tools. Overall, the trends predicted by the FEP calculations were well borne out by the assay results. FEP-guided lead optimization is confirmed as a valuable tool for molecular design including drug discovery; chlorine scans are particularly attractive since they are both straightforward to perform and highly informative.
Subject(s)
Azoles/chemistry , Azoles/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/enzymology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Azoles/chemical synthesis , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/genetics , HIV-1/genetics , Models, Molecular , Monte Carlo Method , Mutation , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Oxazoles/chemical synthesis , Oxazoles/chemistry , Oxazoles/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Structure-Activity Relationship , ThermodynamicsABSTRACT
During the 2003 severe acute respiratory syndrome (SARS) outbreak in Toronto, the potential introduction of SARS into the homeless population was a serious concern. Although no homeless individual in Toronto contracted SARS, the outbreak highlighted the need to develop an outbreak preparedness plan that accounts for unique issues related to homeless people. We conducted key informant interviews with homeless service providers and public health officials (n = 17) and identified challenges specific to the homeless population in the areas of communication, infection control, isolation and quarantine, and resource allocation. Planning for future outbreaks should take into account the need to (1) develop systems that enable rapid two-way communication between public health officials and homeless service providers, (2) ensure that homeless service providers have access to infection control supplies and staff training, (3) prepare for possible homeless shelter closures due to staff shortages or high attack rates among clients, and (4) plan for where and how clinically ill homeless individuals will be isolated and treated. The Toronto SARS experience provided insights that are relevant to response planning for future outbreaks in cities with substantial numbers of homeless individuals.
