AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Crystal Structure of a Monomeric Thiolase-Like Protein Type 1 (TLP1) from <em>Mycobacterium smegmatis</em>

<div><p>An analysis of the <em>Mycobacterium smegmatis</em> genome suggests that it codes for several thiolases and thiolase-like proteins. Thiolases are an important family of enzymes that are involved in fatty acid metabolism. They occur as either dimers or tetramers. Thiolases catalyze the Claisen condensation of two acetyl-Coenzyme A molecules in the synthetic direction and the thiolytic cleavage of 3-ketoacyl-Coenzyme A molecules in the degradative direction. Some of the <em>M. smegmatis</em> genes have been annotated as thiolases of the poorly characterized SCP2-thiolase subfamily. The mammalian SCP2-thiolase consists of an N-terminal thiolase domain followed by an additional C-terminal domain called sterol carrier protein-2 or SCP2. The <em>M. smegmatis</em> protein selected in the present study, referred to here as the thiolase-like protein type 1 (<em>Ms</em>TLP1), has been biochemically and structurally characterized. Unlike classical thiolases, <em>Ms</em>TLP1 is a monomer in solution. Its structure has been determined at 2.7 Å resolution by the single wavelength anomalous dispersion method. The structure of the protomer confirms that the N-terminal domain has the thiolase fold. An extra C-terminal domain is indeed observed. Interestingly, it consists of six β-strands forming an anti-parallel β-barrel which is completely different from the expected SCP2-fold. Detailed sequence and structural comparisons with thiolases show that the residues known to be essential for catalysis are not conserved in <em>Ms</em>TLP1. Consistent with this observation, activity measurements show that <em>Ms</em>TLP1 does not catalyze the thiolase reaction. This is the first structural report of a monomeric thiolase-like protein from any organism. These studies show that <em>Ms</em>TLP1 belongs to a new group of thiolase related proteins of unknown function.</p> </div

Long-term electricity demand forecast and supply side scenarios for Pakistan (2015–2050): A LEAP model application for policy analysis

Pakistan is facing electricity crises owing to lack of integrated energy planning, reliance on imported fuels for power generation, and poor governance. This situation has challenged governments for over a decade to address these crises. However, despite various conformist planning and policy initiatives, the balance between demand and supply of electricity is yet to be achieved. In this study, Long-range Energy Alternatives Planning System (LEAP) is used to develop Pakistan's LEAP modeling framework for the period 2015–2050. Following demand forecast, four supply side scenarios; Reference (REF), Renewable Energy Technologies (RET), Clean Coal Maximum (CCM) and Energy Efficiency and Conservation (EEC) are enacted considering resource potential, techno-economic parameters, and CO2 emissions. The model results estimate the demand forecast of 1706.3 TWh in 2050, at an annual average growth rate of 8.35%, which is 19 times higher than the base year demand. On the supply side, RET scenario, although capital-intensive earlier in the modeling period, is found to be the sustainable electricity generation path followed by EEC scenario with the lower demand of 1373.2 TWh and minimum Net Present Value (NPV) at an aggregate discount rate of 6%. Conclusion section of the paper provides the recommendations devised from this study results

Cloning, expression, purification and preliminary X-ray diffraction studies of a putative Mycobacterium smegmatis thiolase

Thiolases are important in fatty-acid degradation and biosynthetic pathways. Analysis of the genomic sequence of Mycobacterium smegmatis suggests the presence of several putative thiolase genes. One of these genes appears to code for an SCP-x protein. Human SCP-x consists of an N-terminal domain (referred to as SCP2 thiolase) and a C-terminal domain (referred as sterol carrier protein 2). Here, the cloning, expression, purification and crystallization of this putative SCP-x protein from M. smegmatis are reported. The crystals diffracted X-rays to 2.5 Å resolution and belonged to the triclinic space group P1. Calculation of rotation functions using X-ray diffraction data suggests that the protein is likely to possess a hexameric oligomerization with 32 symmetry which has not been observed in the other six known classes of this enzyme

Crystal Structures of SCP2 Thiolases of Trypanosomatidae, Human Pathogens Causing Widespread Tropical Diseases The Importance for Catalysis of the Cysteine of the Unique Hdcf Loop.

Thiolases are essential CoA-dependent enzymes in lipid metabolism. In the present study we report the crystal structures of trypanosomal and leishmanial SCP2 (sterol carrier protein, type-2)-thiolases. Trypanosomatidae cause various widespread devastating (sub)-tropical diseases, for which adequate treatment is lacking. The structures reveal the unique geometry of the active site of this poorly characterized subfamily of thiolases. The key catalytic residues of the classical thiolases are two cysteine residues, functioning as a nucleophile and an acid/base respectively. The latter cysteine residue is part of a CxG motif. Interestingly, this cysteine residue is not conserved in SCP2-thiolases. The structural comparisons now show that in SCP2-thiolases the catalytic acid/base is provided by the cysteine residue of the HDCF motif, which is unique for this thiolase subfamily. This HDCF cysteine residue is spatially equivalent to the CxG cysteine residue of classical thiolases. The HDCF cysteine residue is activated for acid/base catalysis by two main chain NH-atoms, instead of two water molecules, as present in the CxG active site. The structural results have been complemented with enzyme activity data, confirming the importance of the HDCF cysteine residue for catalysis. The data obtained suggest that these trypanosomatid SCP2-thiolases are biosynthetic thiolases. These findings provide promise for drug discovery as biosynthetic thiolases catalyse the first step of the sterol biosynthesis pathway that is essential in several of these parasites.</jats:p

The overall fold of <i>Ms</i>TLP1.

<p>A) The TLP protomer is divided into two domains. The N-terminal thiolase domain can further be divided into an N-terminal half (green), a thiolase loop region (light blue) and a C-terminal half (dark). The C-terminal extra domain of <i>Ms</i>TLP1 is in dark green. The two domains are connected by a linker region (yellow). B) The N-terminal thiolase domain of <i>Ms</i>TLP1 has the conserved fold of the thiolase superfamily. The two β sheets are sandwiched between three layers of α helices forming the characteristic α/β/α/β/α layered structure found in classical thiolases. The numbering of the strands and helices conforms to the assignment in the classical thiolases.</p

The putative CoA binding groove of <i>Ms</i>TLP1 from the comparison with the <i>Z. ramigera</i> thiolase.

<p>A) The shape of the binding groove. The binding mode of acetyl CoA (red) as obtained by superposition of the complexed <i>Z. ramigera</i> thiolase structure. The N-terminal thiolase domain is shown in pale blue and the C-terminal domain is shown in green. Also highlighted in blue are the positively charged residues Arg227, Arg240, and Arg248 which line the putative CoA binding pocket. B). The disordered loops. Loop regions that are disordered in <i>Ms</i>TLP1 but ordered in <i>Z. ramigera</i> thiolase are highlighted in blue. Also included in the <i>Z. ramigera</i> reference structure is the loop just before the dimer interface Nβ3 strand (residues 73–83) of the adjacent subunit (red). This superposition shows that the linker region of <i>Ms</i>TLP1 clashes with this loop, thereby preventing the formation of <i>Z.ramigera</i> thiolase-like dimers.</p