Due to extensive bioprospecting efforts of the past and technology factors, there have been questions about drug discovery prospect from untapped species. We analyzed recent trends of approved drugs derived from previously untapped species, which show no sign of untapped drug-productive species being near extinction and suggest high probability of deriving new drugs from new species in existing drug-productive species families and clusters. Case histories of recently approved drugs reveal useful strategies for deriving new drugs from the scaffolds and pharmacophores of the natural product leads of these untapped species. New technologies such as cryptic gene-cluster exploration may generate novel natural products with highly anticipated potential impact on drug discovery.

There have been renewed interests in natural products as drug discovery sources. In particular, natural product combinations have been extensively studied, clinically tested, and widely used in traditional, folk and alternative medicines. But opinions about their therapeutic efficacies vary from placebo to synergistic effects. The important questions are whether synergistic effects can sufficiently elevate therapeutic potencies to drug levels, and by what mechanisms and at what odds such combinations can be assembled. We studied these questions by analyzing literature-reported cell-based potencies of 190 approved anticancer and antimicrobial drugs, 1378 anticancer and antimicrobial natural products, 99 natural product extracts, 124 synergistic natural product combinations, and 122 molecular interaction profiles of the 19 natural product combinations with collective potency enhanced to drug level or by >10-fold. Most of the evaluated natural products and combinations are sub-potent to drugs. Sub-potent natural products can be assembled into combinations of drug level potency at low probabilities by distinguished multi-target modes modulating primary targets, their regulators and effectors, and intracellular bioavailability of the active natural products.