de novo Design and in silico Optimization of Antibody-Like Binders Targeting Ebola Viral Antigen

At the end of 2019, the world was struck by the COVID-19 pandemic, which resulted in dire repercussions of unimaginable proportions. From the beginning, the international scientific community employed several strategies to tackle the spread of this disease. Most notably, these consisted of the development of a COVID-19 vaccine and the discovery of antiviral agents through the repositioning of already known drugs with methods such as de novo design. Previously, methylthiomorphic compounds, designed by our group as antihypertensive agents, have been shown to display an affinity with the ACE2 (angiotensin converting enzyme) receptor, a key mechanism required for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) entry into target cells. Therefore, the objective of this work consists of evaluating, in silico, the inhibitory activity of these compounds between the ACE2 receptor and the S1 subunit of the SARS-CoV-2 spike protein. Supported by the advances of different research groups on the structure of the coronavirus spike and the interaction of the latter with its receptor, ACE2, we carried out a computational study that examined the effect of in-house designed compounds on the inhibition of said interaction. Our results indicate that the polyphenol LQM322 is one of the candidates that should be considered as a possible anti-COVID-19 agent.

Download Full-text

Target-templated de novo design of macrocyclic d-/l-peptides: discovery of drug-like inhibitors of PD-1

Chemical Science ◽

10.1039/d1sc01031j ◽

2021 ◽

Vol 12 (14) ◽

pp. 5164-5170

Author(s):

Salvador Guardiola ◽

Monica Varese ◽

Xavier Roig ◽

Macarena Sánchez-Navarro ◽

Jesús García ◽

...

Keyword(s):

Specific Surface ◽

Protein Interactions ◽

In Silico ◽

Cyclic Peptides ◽

De Novo ◽

De Novo Design ◽

Target Protein ◽

Surface Patch ◽

Protein Protein Interactions

In silico design of heterochiral cyclic peptides that bind to a specific surface patch on the target protein (PD-1, in this case) and disrupt protein–protein interactions.

Download Full-text

De Novo Design of Protein Kinase Inhibitors by in Silico Identification of Hinge Region-Binding Fragments

ACS Chemical Biology ◽

10.1021/cb300729y ◽

2013 ◽

Vol 8 (5) ◽

pp. 1044-1052 ◽

Cited By ~ 30

Author(s):

Robert Urich ◽

Grant Wishart ◽

Michael Kiczun ◽

André Richters ◽

Naomi Tidten-Luksch ◽

...

Keyword(s):

Protein Kinase ◽

In Silico ◽

Kinase Inhibitors ◽

De Novo ◽

De Novo Design ◽

Protein Kinase Inhibitors ◽

Hinge Region ◽

In Silico Identification

Download Full-text

Fragment-Based Drug Design of Antitumoral Molecules Polo-like kinase 1 inhibitors: in-silico approach

Letters in Drug Design & Discovery ◽

10.2174/1570180818999201230195526 ◽

2020 ◽

Vol 18 ◽

Author(s):

Ayoub Attoui ◽

Widad Sobhi ◽

Nour El Houda Hammoudi ◽

Yacine Benguerba

Keyword(s):

Development Strategy ◽

In Silico ◽

De Novo ◽

Pharmacophore Model ◽

De Novo Design ◽

Ligand Complex ◽

Docking Simulations ◽

Virtual Database ◽

Promising Strategy ◽

Therapeutic Development

Background:: Kinase enzymes are reported to be very implicated in cancer. Polo-like kinase 1 (PLK1) is a protein kinase with a marked role in tumorigenesis and its inhibition is a promising anticancer therapeutic development strategy. Objective:: The purpose of this study was de novo design of new PLK1 inhibitors using in-silico approach. Method:: A virtual compounds library based on known inhibitors was designed using BREED algorithm. Molecules were geometry optimized then filtered according to lead-like properties using QiqProp. Receptor-ligand complex-based pharmacophore model was generated with Phase and used to virtually screen the new virtual database. Glide multistage molecular docking simulations were performed for the resulted compounds followed with a Prime MM-GBSA minimization. Results:: Two compounds (prd-comp 1-2) showed acceptable binding poses with a higher docking score than known inhibitor BI2536. MM-GBSA study confirmed that the leads have better binding energy than reference ligands. All leads bind to the key amino acids Cys133, Leu59, with a focus on molecule prd-comp1, proposed to have better affinity due to direct H-bond with Asp194. Conclusion:: Modifying hydration pattern of target protein by displacing water molecule is suggested to be a promising strategy for designing new PLK1 inhibitors. This applied methodology and the retrieved hits could be useful in the design of potent inhibitors of PLK1 as antitumoral agents.

Download Full-text

De novo design and in-silico studies of novel bis-arylpiperazine derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase

JOURNAL OF PHARMACEUTICAL CHEMISTRY ◽

10.14805/jphchem.2014.art10 ◽

2014 ◽

Vol 1 (2) ◽

pp. 22

Author(s):

Ashok Yadav ◽

Subhash Chander ◽

Hiren Lathiya ◽

Hardik Sharma ◽

Kriti Goyal ◽

...

Keyword(s):

Reverse Transcriptase ◽

In Silico ◽

De Novo ◽

De Novo Design ◽

In Silico Studies ◽

Nucleoside Inhibitors ◽

Hiv 1

Download Full-text

In silico de novo design of novel NNRTIs: a bio-molecular modelling approach

RSC Advances ◽

10.1039/c4ra15478a ◽

2015 ◽

Vol 5 (19) ◽

pp. 14814-14827 ◽

Cited By ~ 8

Author(s):

Nilanjana Jain (Pancholi) ◽

Swagata Gupta ◽

Neelima Sapre ◽

Nitin S. Sapre

Keyword(s):

Interaction Potential ◽

Molecular Modelling ◽

In Silico ◽

De Novo ◽

De Novo Design ◽

High Efficacy ◽

Structural Requirements ◽

Structural Descriptors ◽

Modelling Approach

Six novel NNRTIs (DABO) with high efficacy are designed by assessing the interaction potential and structural requirements using chemometric analyses (SVM, BPNN and MLR) on structural descriptors.

Download Full-text