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The entry of HIV-1 into permissive cells, facilitated by the Env complex, is a complex series of events and the inhibition of HIV-1 entry is an attractive, yet underexploited therapeutic approach. Using the combination of a field-derived bioactive conformation template to perform virtual screening and iterative bioisosteric replacements, coupled with in silico predictions of absorption, distribution, metabolism, and excretion, we have identified new leads for HIV-1 entry inhibitors. Moreover, we have characterized the mechanism of action of a representative compound and discovered that it likely functions via an allosteric mechanism to prevent conformational changes required for fusion/entry. These inhibitory compounds therefore represent novel reagents that can be used to probe the mechanism of entry of HIV-1 into the host cell and hold promise for the development of a new class of anti-HIV agents.