Protein Binding Pocket Optimization for Virtual High-Throughput Screening (vHTS) Drug Discovery

Dimitris Gazgalis, Mehreen Zaka, Mehreen Zaka, Bilal Haider Abbasi, Diomedes E. Logothetis, Mihaly Mezei, Meng Cui

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


The virtual high-throughput screening (vHTS) approach has been widely used for large database screening to identify potential lead compounds for drug discovery. Due to its high computational demands, docking that allows receptor flexibility has been a challenging problem for virtual screening. Therefore, the selection of protein target conformations is crucial to produce useful vHTS results. Since only a single protein structure is used to screen large databases in most vHTS studies, the main challenge is to reduce false negative rates in selecting compounds for in vitro tests. False negatives are most likely to occur when using apo structures or homology models of protein targets due to the small volume of the binding pocket formed by incorrect side-chain conformations. Even holo protein structures can exhibit high false negative rates due to ligand-induced fit effects, since the shape of the binding pocket highly depends on its bound ligand. To reduce false negative rates and improve success rates for vHTS in drug discovery, we have developed a new Monte Carlo-based approach that optimizes the binding pocket of protein targets. This newly developed Monte Carlo pocket optimization (MCPO) approach was assessed on several datasets showing promising results. The binding pocket optimization approach could be a useful tool for vHTS-based drug discovery, especially in cases when only apo structures or homology models are available.

Original languageEnglish
Pages (from-to)14297-14307
Number of pages11
JournalACS Omega
Issue number24
StatePublished - 23 Jun 2020


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