ORIGINAL PAPER Virtual screening to identify Leishmania braziliensis N-myristoyltransferase inhibitors: pharmacophore models, docking, and molecular dynamics Juliana Cecília de Carvalho Gallo 1,2 & Larissa de Mattos Oliveira 1,2 & Janay Stefany Carneiro Araújo 1,2 & Isis Bugia Santana 1,3 & Manoelito Coelho dos Santos Junior 1,2,3 Received: 25 March 2018 /Accepted: 12 August 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Leishmaniasis is caused by several protozoa species belonging to genus Leishmania that are hosted by humans and other mammals. Millions of new cases are recorded every year and the drugs available on the market do not show satisfactory efficacy and safety. A hierarchical virtual screening approach based on the pharmacophore model, molecular docking, and molecular dynamics was conducted to identify possible Leishmania braziliensis N-misristoyltransferase (LbNMT) inhibitors. The adopted pharmacophore model had three main features: four hydrophobic centers, four hydrogen-bond acceptor atoms, and one positive nitrogen center. The molecules (n=15,000) were submitted to alignment with the pharmacophore model and only 27 molecules aligned to model. Six molecules were submitted to molecular docking, using receptor PDB ID 5A27. After docking, the ZINC35426134 was a top-ranked molecule (- 64.61 kcal/mol). The molecule ZINC35426134 shows hydrophobic interactions with Phe82, Tyr209, Val370, and Leu391 and hydrogen bonds with Asn159, Tyr318, and Val370. Molecular dynamics simula- tions were performed with the protein in its APO and HOLO forms for 37 ns in order to assess the stability of the protein–ligand complex. Results showed that the HOLO form was more stable than the APO one, and it suggests that the ZINC35426134 binding stabilizes the enzyme. Therefore, the selected molecule has the potential to meet the herein proposed target. Keywords Leishmania braziliensis . N-myristoyltransferase . Pharmacophore model . Molecular docking . Natural products . Molecular dynamics Introduction Cutaneous leishmaniasis is a neglected tropical disease mainly caused by Leishmania braziliensis, which is also responsible for mucosal leishmaniasis. The current pharmacological treat- ment has limitations, such as toxicity and administration dif- ficulties [1]. Therefore, new therapeutic alternatives are nec- essary [2] to help identify new drugs that act on specific tar- gets without any cross-resistance to the existing drugs [3]. Leishmania braziliensis N-myristoyltransferase (LbNMT) is an enzyme responsible for transferring myristate from the myristoyl-coA substrate to the N-terminal glycine of proteins [4]. It was chosen as a target because it is responsible for signaling viability and normal cell growth [5]; therefore, it must be a valid target [6]. Virtual screening techniques can satisfactorily optimize the selection of potential drugs, besides its significant cost and time reduction [7]. Hierarchical virtual screening can be of two types: ligand-based (LBVS) or structure-based (SBVS). LBVS selects compounds through similarity anal- ysis, since it is capable of showing their physical-chemical and structural properties, as well as pharmacophore charac- teristics and electrostatic potential. In contrast, SBVS This paper belongs to Topical Collection XIX - Brazilian Symposium of Theoretical Chemistry (SBQT2017) * Juliana Cecília de Carvalho Gallo julianaccgallo@gmail.com 1 Laboratório de Modelagem Molecular, Universidade Estadual de Feira de Santana, Feira de Santana, Brazil 2 Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual de Feira de Santana, Feira de Santana, Brazil 3 Programa de Pós-Graduação em Biotecnologia, Universidade Estadual de Feira de Santana, Feira de Santana, Brazil Journal of Molecular Modeling (2018) 24:260 https://doi.org/10.1007/s00894-018-3791-8